JP2023519549A - Oral composition containing longan meat-containing mixed herbal extract and its use for treating or improving inflammatory disease - Google Patents

Oral composition containing longan meat-containing mixed herbal extract and its use for treating or improving inflammatory disease Download PDF

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JP2023519549A
JP2023519549A JP2022555655A JP2022555655A JP2023519549A JP 2023519549 A JP2023519549 A JP 2023519549A JP 2022555655 A JP2022555655 A JP 2022555655A JP 2022555655 A JP2022555655 A JP 2022555655A JP 2023519549 A JP2023519549 A JP 2023519549A
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extract
present
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ナム パク，オク
イン リュ，ヘ
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Abstract

炎症に関与するサイトカイン（ＲＰＬＰＯ、ＴＳＬＰ、ＧＭ－ＣＳＦおよびＩＬ－１β）の発現阻害効果（実験例１）；ＨＴ－２９およびＴＨＰ－１細胞に対する細胞生存率試験（ｉｎ ｖｉｔｒｏ、実験例２）；ＴＨＰ－１細胞における抗炎症活性（ｉｎ ｖｉｔｒｏ、実験例３）；オートファジー活性抑制効果（ｉｎ ｖｉｔｒｏ、実験例４）などのｉｎ ｖｉｔｒｏ実験だけでなく、関節炎誘発ラット動物モデルを用いた関節炎抑制効果（ｉｎ ｖｉｖｏ、実験例５）などのｉｎ ｖｉｖｏ実験を行うことにより、本発明の組み合わせ組成物の抗炎症／抗リウマチ効果が強力であることが立証された。したがって、本発明の混合抽出物は、経口用医薬組成物の形態として炎症性疾患および関節炎疾患の改善または治療に非常に有用であることが確認された。【選択図】なしExpression inhibitory effect of cytokines involved in inflammation (RPLPO, TSLP, GM-CSF and IL-1β) (Experimental Example 1); Cell viability test for HT-29 and THP-1 cells (in vitro, Experimental Example 2); Anti-inflammatory activity in THP-1 cells (in vitro, Experimental Example 3); not only in vitro experiments such as autophagy activity inhibitory effect (in vitro, Experimental Example 4), but also arthritis inhibitory effect using arthritis-induced rat animal models By performing in vivo experiments such as (in vivo, Experimental Example 5), it was demonstrated that the anti-inflammatory/anti-rheumatic effect of the combination composition of the present invention is potent. Therefore, it was confirmed that the mixed extract of the present invention, in the form of an oral pharmaceutical composition, is very useful for ameliorating or treating inflammatory diseases and arthritic diseases. [Selection figure] None

Description

本発明は、炎症性疾患の治療または予防のための竜眼肉（Ｌｏｎｇａｎａｅ Ａｒｉｌｌｕｓ）を含む混合生薬抽出物を含む経口用医薬組成物およびその使用に関する。 The present invention relates to an oral pharmaceutical composition comprising a mixed herbal extract containing Longanae Arillus and its use for the treatment or prevention of inflammatory diseases.

一般に、炎症反応とは、組織や細胞が侵襲を受け、組織や細胞に何らかの有機的変化が生じた場合に、浮腫や痛みなどを伴う人体の正常な反応である。近年、様々な種類のサイトカインが炎症性疾患に関与していることが明らかになった。 Generally, inflammatory reaction is a normal reaction of the human body accompanied by edema, pain, etc., when tissues or cells are invaded and some organic change occurs in the tissues or cells. In recent years, it has become clear that various types of cytokines are involved in inflammatory diseases.

したがって、好中球などのような炎症細胞によって分泌され、炎症、アレルギー反応、または喘息などの発生によって引き起こされるシステムである、ロイコトリエン生合成を引き起こす炎症細胞の活性化に関与するＩＬ－４、ＩＬ－５、およびＩＬ－１３、および免疫グロブリンＥなどの様々なサイトカインの産生を阻害することに有効な薬物を開発するため、多くの研究が進められてきた。 Thus, IL-4, IL involved in the activation of inflammatory cells to trigger leukotriene biosynthesis, a system secreted by inflammatory cells such as neutrophils and triggered by inflammation, allergic reactions, or development of asthma, etc. Much research has been done to develop drugs that are effective in inhibiting the production of various cytokines such as IL-5, and IL-13, and immunoglobulin E.

炎症期がＴＮＦ－α、ＩＬ－１β、ＩＬ－６などのプロ炎症誘発性サイトカインとＭＭＰ（ＰＤＧＦ、ＶＥＧＦ、およびＩＧＦなどのマトリックスメタロプロテイナーゼ）によって進行しているのに対し、成長因子の発現は減少することが知られている（Ｔｒｅｎｇｏｖｅ ＮＪ， Ｂｉｅｌｅｆｅｌｄｔ－Ｏｈｍａｎｎ Ｈ， Ｓｔａｃｅｙ ＭＣ （２００１） Ｍｉｔｏｇｅｎｉｃ ａｃｔｉｖｉｔｙ ａｎｄ ｃｙｔｏｋｉｎｅ ｌｅｖｅｌｓ ｉｎ ｎｏｎ－ｈｅａｌｉｎｇ ａｎｄ ｈｅａｌｉｎｇ ｃｈｒｏｎｉｃ ｌｅｇ ｕｌｃｅｒｓ． Ｗｏｕｎｄ Ｒｅｐａｉｒ ａｎｄ Ｒｅｇｅｎｅｒａｔｉｏｎ． ８： １３－２５．； Ａｒｍｓｔｒｏｎｇ ＤＧ， Ｊｕｄｅ ＥＢ （２００２） Ｔｈｅ Ｒｏｌｅ ｏｆ Ｍａｔｒｉｘ Ｍｅｔａｌｌｏｐｒｏｔｅｉｎａｓｅｓ ｉｎ Ｗｏｕｎｄ Ｈｅａｌｉｎｇ． Ｊｏｕｒｎａｌ ｏｆ ｔｈｅ Ａｍｅｒｉｃａｎ Ｐｏｄｉａｔｒｉｃ Ｍｅｄｉｃａｌ Ａｓｓｏｃｉａｔｉｏｎ． ９２：１２－１８．）。 The inflammatory phase is driven by pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6 and MMPs (matrix metalloproteinases such as PDGF, VEGF and IGF), whereas growth factor expression is (Trengove NJ, Bielefeldt-Ohmann H, Stacey MC (2001) Mitogenic activity and cytokine levels in non-healing and healing chronic leg ulcers. Wound R Epair and Regeneration.8: 13-25. DG, Jude EB (2002) The Role of Matrix Metalloproteinases in Wound Healing. Journal of the American Podiatric Medical Association. 92:12-18.).

ＭＭＰ（マトリックスメタロプロテイナーゼ）は、創傷部位のＴＩＭＰ（メタロプロテイナーゼの組織阻害剤）によって制御され、これは細胞外基質を分解し、再上皮化（ｒｅ－ｅｐｉｔｈｅｌｉａｌｉｚａｔｉｏｎ）を可能にする（Ｍａｒｔｉｎｓ ＶＬ， Ｃａｌｅｙ Ｍ， Ｏ’ Ｔｏｏｌｅ ＥＡ （２０１３） Ｍａｔｒｉｘ ｍｅｔａｌｌｏｐｒｏｔｅｉｎａｓｅｓ ａｎｄ ｅｐｉｄｅｒｍａｌ ｗｏｕｎｄ ｒｅｐａｉｒ． Ｃｅｌｌ ａｎｄ Ｔｉｓｓｕｅ Ｒｅｓｅａｒｃｈ． ３５１：２５５－２６８）。 MMPs (matrix metalloproteinases) are regulated by TIMPs (tissue inhibitors of metalloproteinases) at the wound site, which degrade the extracellular matrix and allow re-epithelialization (Martins VL, Caley M, O'Toole EA (2013) Matrix metalloproteinases and epidermal wound repair. Cell and Tissue Research. 351:255-268).

特に、ＭＭＰの中でも慢性創傷に最も有害な影響を及ぼすとして知られているＭＭＰ－９についての研究が集中している（Ｊｏｎｅｓ ＪＩ， Ｎｇｕｙｅｎ ＴＴ， Ｐｅｎｇ Ｚ， Ｃｈａｎｇ Ｍ （２０１９） Ｔａｒｇｅｔｉｎｇ ＭＭＰ－９ ｉｎ Ｄｉａｂｅｔｉｃ Ｆｏｏｔ Ｕｌｃｅｒｓ． Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ． １２： ７９．； Ｒｅｉｓｓ ＭＪ， Ｈａｎ ＹＰ， Ｇａｒｃｉａ Ｅ， Ｇｏｌｄｂｅｒｇ Ｍ， Ｙｕ Ｈ， Ｇａｒｎｅｒ ＷＬ （２０１０） Ｍａｔｒｉｘ ｍｅｔａｌｌｏｐｒｏｔｅｉｎａｓｅ－９ ｄｅｌａｙｓ ｗｏｕｎｄ ｈｅａｌｉｎｇ ｉｎ ａ ｍｕｒｉｎｅ ｗｏｕｎｄ ｍｏｄｅｌ． Ｓｕｒｇｅｒｙ． １４７：２９５－３０２．）。 In particular, research is focused on MMP-9, which is known to have the most detrimental effect on chronic wounds among MMPs (Jones JI, Nguyen TT, Peng Z, Chang M (2019) Targeting MMP-9 in Diabetic Foot Ulcers Pharmaceuticals 12: 79; Reiss MJ, Han YP, Garcia E, Goldberg M, Yu H, Garner WL (2010) Matrix metalloproteinase-9 delays wound healing in a murine wound model.Surgery.147:295- 302.).

したがって、炎症性疾患を治療および改善する上で、天然由来原料から従来使用されてきた薬物よりも副作用が少ない、炎症性疾患を治療および改善するためのより効果的な薬物および化粧品を開発することが依然として必要とされている。 Therefore, to develop more effective drugs and cosmetics for treating and ameliorating inflammatory diseases, which have fewer side effects than drugs conventionally used from naturally derived raw materials in treating and ameliorating inflammatory diseases. is still needed.

ムクロジ科（Ｓａｐｉｎｄａｃｅａｅ）に属するラムヤイ（Ｄｉｍｏｃａｒｐｕｓ ｌｏｎｇａｎ）、リュウガン（Ｅｕｐｈｏｒｉａ ｌｏｎｇａｎ）または同種の種皮である、竜眼肉（Ｌｏｎｇａｎａｅ Ａｒｉｌｌｕｓ）は、グルコース、フルクトース、タンパク質などを含有し、心筋保護効果、食欲増進効果などを示すことが報告されている（Ｃｈｕｎｇ Ｂ． Ｓ ｅｔ ａｌ， Ｄｏｈａｅｈｙａｎｇｙａｋｄａｅｓａｊｅｏｎ，ｙｏｕｎｇｒｉｍｓａ， ２ｎｄ Ｅｄ．ｐ１９７－１９８，１９９８）。 Dimocarpus longan belonging to the Sapindaceae family, Euphoria longan, or Longanae Arillus, which is the seed coat of the same species, contains glucose, fructose, protein, etc., and has myocardial protective effect, appetite stimulating effect, etc. (Chung B. S et al, Dohaehyangyakdaesajeon, youngrimsa, 2nd Ed. p197-198, 1998).

セリ科（Ｕｍｂｅｌｌｉｆｅｒａｅ）に属するＬｉｇｕｓｔｉｃｕｍ ｔｅｎｕｉｓｓｉｍｕｍ Ｋｉｔａｇａｗａ、Ｌｉｇｕｓｔｉｃｕｍ ｓｉｎｅｎｓｅ Ｏｌｉｖ、Ｌｉｇｕｓｔｉｃｕｍ ｊｅｈｏｌｅｎｓｅ Ｎａｋａｉ ｅｔ Ｋｉｔａｇａｗａまたは同種の根茎または根である藁本（Ｌｉｇｕｓｔｉｃｉ Ｔｅｎｕｉｓｓｉｍｉ Ｒｈｉｚｏｍａ）は、クニジリド（ｃｎｉｄｉｌｉｄｅ）、３－ブチルフタリド（ｐｈｔｈａｌｉｄｅ）などを含有し、抗菌効果などを示すことが報告されている（Ｃｈｕｎｇ Ｂ． Ｓ ｅｔ ａｌ， Ｄｏｈａｅ－ｈｙａｎｇｙａｋｄａｅｓａｊｅｏｎ，ｙｏｕｎｇｒｉｍｓａ，２ｎｄ Ｅｄ．Ｐ４２８－４２９，１９９８）。 Ligusticum tenuissimum Kitagawa, Ligusticum sinense Oliv, Ligusticum jeholense Nakai et Kitagawa belonging to the Umbelliferae family (Umbelliferae) or the rhizome or root of the same species Ligustici Tenuissimi Rhizo ma) includes cnidilide, 3-butylphthalide, etc. (Chung B. S et al, Dohae-hyangyakdaesajeon, youngrimsa, 2nd Ed. P428-429, 1998).

ヒメハギ科（Ｐｏｌｙｇａｌａｃｅａｅ）に属するイトヒメハギ（Ｐｏｌｙｇａｌａ ｔｅｎｕｉｆｏｌｉａ Ｗｉｌｌｄ）または同種の根であるオンジ（Ｐｏｌｙｇａｌａｅ ｒａｄｉｘ）は、様々なサポニンを含有し、去痰作用、抗菌作用などを示すことが報告されている（Ｃｈｕｎｇ Ｂ． Ｓ ｅｔ ａｌ， Ｄｏｈａｅｈｙａｎｇｙａｋｄａｅｓａｊｅｏｎ，ｙｏｕｎｇｒｉｍｓａ，２ｎｄ Ｅｄ．Ｐ７９８－７９９，１９９８）。 It has been reported that Polygala tenuifolia Willd, which belongs to the Polygalaceae family, or Polygalae radix, the root of the same species, contains various saponins and exhibits expectorant and antibacterial effects (Chung B. S et al, Dohaehyangyakdaesajeon, youngrimsa, 2nd Ed. P798-799, 1998).

しかし、その開示内容が本発明に引用され含まれた上記引用文献のどこにも、炎症性疾患に対する強力な治療効果を示す竜眼肉、藁本およびオンジを経口用として適用する混合生薬抽出物の予防または改善活性についての報告または開示がされていない。 However, nowhere in the above-cited references whose disclosure is cited and included in the present invention is mentioned prophylactic or mixed herbal extracts applied orally of Longan, Strawberry and Onji showing potent therapeutic effects against inflammatory diseases. No improvement activity was reported or disclosed.

Ｔｒｅｎｇｏｖｅ ＮＪ， Ｂｉｅｌｅｆｅｌｄｔ－Ｏｈｍａｎｎ Ｈ， Ｓｔａｃｅｙ ＭＣ （２００１） Ｍｉｔｏｇｅｎｉｃ ａｃｔｉｖｉｔｙ ａｎｄ ｃｙｔｏｋｉｎｅ ｌｅｖｅｌｓ ｉｎ ｎｏｎ－ｈｅａｌｉｎｇ ａｎｄ ｈｅａｌｉｎｇ ｃｈｒｏｎｉｃ ｌｅｇ ｕｌｃｅｒｓ． Ｗｏｕｎｄ Ｒｅｐａｉｒ ａｎｄ Ｒｅｇｅｎｅｒａｔｉｏｎ． ８： １３－２５．； Ａｒｍｓｔｒｏｎｇ ＤＧ， Ｊｕｄｅ ＥＢ （２００２） Ｔｈｅ Ｒｏｌｅ ｏｆ Ｍａｔｒｉｘ Ｍｅｔａｌｌｏｐｒｏｔｅｉｎａｓｅｓ ｉｎ Ｗｏｕｎｄ Ｈｅａｌｉｎｇ． Ｊｏｕｒｎａｌ ｏｆ ｔｈｅ Ａｍｅｒｉｃａｎ Ｐｏｄｉａｔｒｉｃ Ｍｅｄｉｃａｌ Ａｓｓｏｃｉａｔｉｏｎ． ９２：１２－１８。Trengové NJ, Bielefeldt-Ohmann H, Stacey MC (2001) Mitogenic activity and cytokine levels in non-healing and healing chronic legs. Wound Repair and Regeneration. 8: 13-25. Armstrong DG, Jude EB (2002) The Role of Matrix Metalloproteinases in Wound Healing. Journal of the American Podiatric Medical Association. 92:12-18. Ｍａｒｔｉｎｓ ＶＬ， Ｃａｌｅｙ Ｍ， Ｏ’ Ｔｏｏｌｅ ＥＡ （２０１３） Ｍａｔｒｉｘ ｍｅｔａｌｌｏｐｒｏｔｅｉｎａｓｅｓ ａｎｄ ｅｐｉｄｅｒｍａｌ ｗｏｕｎｄ ｒｅｐａｉｒ． Ｃｅｌｌ ａｎｄ Ｔｉｓｓｕｅ Ｒｅｓｅａｒｃｈ． ３５１：２５５－２６８。Martins VL, Caley M, O'Toole EA (2013) Matrix metalloproteinases and epidermal wound repair. Cell and Tissue Research. 351:255-268. Ｊｏｎｅｓ ＪＩ， Ｎｇｕｙｅｎ ＴＴ， Ｐｅｎｇ Ｚ， Ｃｈａｎｇ Ｍ （２０１９） Ｔａｒｇｅｔｉｎｇ ＭＭＰ－９ ｉｎ Ｄｉａｂｅｔｉｃ Ｆｏｏｔ Ｕｌｃｅｒｓ． Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ． １２： ７９．； Ｒｅｉｓｓ ＭＪ， Ｈａｎ ＹＰ， Ｇａｒｃｉａ Ｅ， Ｇｏｌｄｂｅｒｇ Ｍ， Ｙｕ Ｈ， Ｇａｒｎｅｒ ＷＬ （２０１０） Ｍａｔｒｉｘ ｍｅｔａｌｌｏｐｒｏｔｅｉｎａｓｅ－９ ｄｅｌａｙｓ ｗｏｕｎｄ ｈｅａｌｉｎｇ ｉｎ ａ ｍｕｒｉｎｅ ｗｏｕｎｄ ｍｏｄｅｌ． Ｓｕｒｇｅｒｙ． １４７：２９５－３０２。Jones JI, Nguyen TT, Peng Z, Chang M (2019) Targeting MMP-9 in Diabetic Foot Ulcers. Pharmaceuticals. 12:79. Reiss MJ, Han YP, Garcia E, Goldberg M, Yu H, Garner WL (2010) Matrix metalloproteinase-9 delays wound healing in a murine wound model. Surgery. 147:295-302. Ｃｈｕｎｇ Ｂ． Ｓ ｅｔ ａｌ， Ｄｏｈａｅｈｙａｎｇｙａｋｄａｅｓａｊｅｏｎ， ｙｏｕｎｇｒｉｍｓａ， ２ｎｄ Ｅｄ． ｐ１９７－１９８， １９９８。ChungB. S et al, Dohaehyangyakdaesajeon, youngrimsa, 2nd Ed. p197-198, 1998. Ｃｈｕｎｇ Ｂ． Ｓ ｅｔ ａｌ， Ｄｏｈａｅｈｙａｎｇｙａｋｄａｅｓａｊｅｏｎ， ｙｏｕｎｇｒｉｍｓａ， ２ｎｄ Ｅｄ． Ｐ４２８－４２９， １９９８。ChungB. S et al, Dohaehyangyakdaesajeon, youngrimsa, 2nd Ed. P428-429, 1998. Ｃｈｕｎｇ Ｂ． Ｓ ｅｔ ａｌ， Ｄｏｈａｅｈｙａｎｇｙａｋｄａｅｓａｊｅｏｎ， ｙｏｕｎｇｒｉｍｓａ， ２ｎｄ Ｅｄ． Ｐ７９８－７９９， １９９８。ChungB. S et al, Dohaehyangyakdaesajeon, youngrimsa, 2nd Ed. P798-799, 1998. Ｊｅｏｎｇ ｅｔ ａｌ．， ２０１９， Ｊ． Ｉｎｖｅｓｔ． Ｄｅｒｍａｔｏｌ．， Ｍａｙ； １３９ （５）：ｐｐ１０９８－１１０９。Jeong et al. , 2019, J.P. Invest. Dermatol. , May; 139(5): pp 1098-1109. Ｋｗｏｎ ＪＹ ｅｔ ａｌ．， Ｓｃｉ Ｒｅｐ． ２０１８ Ｓｅｐ １４；８（１）：１３８３２。Kwon JY et al. , Sci Rep. 2018 Sep 14;8(1):13832. Ｂｕｌｓｔｒａ ＳＫ ｅｔ ａｌ．， １９８９， Ｃｌｉｎ Ｏｒｔｈｏｐ Ｒｅｌａｔ Ｒｅｓ： ２９４－３０２。Bulstra SK et al. , 1989, Clin Orthop Relat Res: 294-302. Ｐｒｉｔｚｋｅｒ Ｋ．Ｐ．Ｈ． ｅｔ ａｌ．， ２００６， Ｏｓｔｅｏａｒｔｈｒｉｔｉｓ Ｃａｒｔｉｌａｇｅ １４：１３－２９。Pritzker K. P. H. et al. , 2006, Osteoarthritis Cartilage 14:13-29.

竜眼肉（Ｌｏｎｇａｎａｅ Ａｒｉｌｌｕｓ）、藁本（Ｌｉｇｕｓｔｉｃｉ Ｔｅｎｕｉｓｓｉｍｉ Ｒｈｉｚｏｍａ）およびオンジ（Ｐｏｌｙｇａｌａｅ ｒａｄｉｘ）の混合生薬抽出物の抗炎症効果を調べるために、本発明者らは炎症に関与するサイトカイン（ＲＰＬＰＯ，ＴＳＬＰ，ＧＭ－ＣＳＦおよびＩＬ－１β）の発現阻害効果（実験例１）；ＨＴ－２９およびＴＨＰ－１細胞に対する細胞生存率試験（ｉｎ ｖｉｔｒｏ、実験例２）；ＴＨＰ－１細胞における抗炎症活性（ｉｎ ｖｉｔｒｏ、実験例３）；オートファジー活性抑制効果（ｉｎ ｖｉｔｒｏ、実験例４）などのｉｎ ｖｉｔｒｏ実験だけでなく、関節炎誘発ラット動物モデルを用いた関節炎抑制効果（ｉｎ ｖｉｖｏ、実験例５）などのｉｎ ｖｉｖｏ実験を含む様々な実験を集中的に行った。これらの調査の結果、本発明者らは、本発明の混合生薬抽出物が炎症疾患を大幅に抑制され、改善したことを確認したことによって最終的に本発明を完成した。 In order to examine the anti-inflammatory effects of mixed herbal extracts of Longanae Arillus, Ligustici Tenuissimi Rhizoma and Polygalae radix, the present inventors investigated cytokines involved in inflammation (RPLPO, TSLP, GM- CSF and IL-1β) expression inhibitory effect (Experimental Example 1); cell viability test for HT-29 and THP-1 cells (in vitro, Experimental Example 2); anti-inflammatory activity in THP-1 cells (in vitro, Experimental Example 3); not only in vitro experiments such as the effect of suppressing autophagy activity (in vitro, Experimental Example 4), but also in vivo experiments such as the inhibitory effect of arthritis using an arthritis-induced rat animal model (in vivo, Experimental Example 5). Various experiments including experiments were conducted intensively. As a result of these investigations, the present inventors have finally completed the present invention by confirming that the mixed crude drug extract of the present invention significantly suppressed and improved inflammatory diseases.

背景技術の問題を解決するための技術的解決策は、炎症性疾患または関節炎疾患を治療および予防するための新規生薬剤形を開発することである。 A technical solution to solve the problems of the background art is to develop new herbal formulations for treating and preventing inflammatory or arthritic diseases.

したがって、本発明の目的は、炎症性疾患を治療および改善するための、竜眼肉（Ｌｏｎｇａｎａｅ Ａｒｉｌｌｕｓ）、藁本（Ｌｉｇｕｓｔｉｃｉ Ｔｅｎｕｉｓｓｉｍｉ Ｒｈｉｚｏｍａ）およびオンジ（Ｐｏｌｙｇａｌａｅ ｒａｄｉｘ）の混合生薬抽出物を有効成分として含む経口用医薬組成物を提供することである。 Therefore, an object of the present invention is to provide an oral preparation containing mixed crude drug extracts of Longanae Arillus, Ligustici Tenuissimi Rhizoma and Polygalae radix as active ingredients for treating and ameliorating inflammatory diseases. It is to provide a pharmaceutical composition.

上述したように、本発明者らは、皮膚炎症に関与するサイトカイン（ＲＰＬＰＯ、ＴＳＬＰ、ＧＭ－ＣＳＦ、ＩＬ－１β）の発現抑制試験（実験例１）；ＨＴ－２９およびＴＨＰ－１細胞に対する細胞生存率試験（ｉｎ ｖｉｔｒｏ、実験例２）；ＴＨＰ－１細胞における抗炎症活性（ｉｎ ｖｉｔｒｏ、実験例３）；オートファジー活性抑制効果（ｉｎ ｖｉｔｒｏ、実験例４）のようなｉｎ ｖｉｔｒｏ実験だけでなく、関節炎誘発ラット動物モデルを用いた関節炎抑制効果（ｉｎ ｖｉｖｏ、実験例５）などのｉｎ ｖｉｖｏ実験を行うことにより、本発明の混合組成物の抗炎症／抗リウマチ効果が強力であることが立証された。したがって、本発明の混合組成物が経口用医薬組成物の形態として炎症性疾患および関節炎疾患の改善または治療に非常に有用であることを確認した。 As described above, the present inventors performed an expression suppression test of cytokines (RPLPO, TSLP, GM-CSF, IL-1β) involved in skin inflammation (Experimental Example 1); Viability test (in vitro, Experimental Example 2); anti-inflammatory activity in THP-1 cells (in vitro, Experimental Example 3); autophagy activity inhibitory effect (in vitro, Experimental Example 4). However, by performing in vivo experiments such as the arthritis-suppressing effect using an arthritis-induced rat animal model (in vivo, Experimental Example 5), it was confirmed that the mixed composition of the present invention has a strong anti-inflammatory/anti-rheumatic effect. Proven. Therefore, it was confirmed that the mixed composition of the present invention, in the form of an oral pharmaceutical composition, is very useful for ameliorating or treating inflammatory diseases and arthritic diseases.

本発明で定義される用語「混合生薬抽出物」は、混合生薬抽出物、すなわち、（ａ）竜眼肉、藁本およびオンジの乾燥重量（ｗ／ｗ）を基準とした混合比が０．０１－１００：０．０１－１００：０．０１－１００重量部（ｗ／ｗ）、好ましくは、０．１－５０：０．１－５０：０．１－５０重量部（ｗ／ｗ）、より好ましくは、０．１－１０：０．１－１０：０．１－１０重量部（ｗ／ｗ）、さらに好ましくは、１－５：１－５：１－５重量部（ｗ／ｗ）、最も好ましくは、１－３：１－３：１－３重量部（ｗ／ｗ）である、竜眼肉、藁本およびオンジの混合生薬抽出物；又は（ｂ）竜眼肉、藁本およびオンジの乾燥重量（ｗ／ｗ）を基準とした混合比が０．０１－１００：０．０１－１００：０．０１－１００重量部（ｗ／ｗ）、好ましくは、０．１－５０：０．１－５０：０．１－５０重量部（ｗ／ｗ）、より好ましくは、０．１－１０：０．１－１０：０．１－１０重量部（ｗ／ｗ）、さらに好ましくは、１－５：１－５：１－５重量部（ｗ／ｗ）、最も好ましくは、１－３：１－３：１－３重量部（ｗ／ｗ）である、竜眼肉、藁本およびオンジの各抽出物の混合物を含む。 The term “mixed herbal extract” defined in the present invention refers to the mixed herbal extract, namely, (a) longan meat, straw book and onji with a mixing ratio of 0.01-0.01 based on dry weight (w/w). 100:0.01-100:0.01-100 parts by weight (w/w), preferably 0.1-50:0.1-50:0.1-50 parts by weight (w/w), more Preferably 0.1-10:0.1-10:0.1-10 parts by weight (w/w), more preferably 1-5:1-5:1-5 parts by weight (w/w) , most preferably, 1-3:1-3:1-3 parts by weight (w/w); A mixing ratio based on weight (w/w) of 0.01-100:0.01-100:0.01-100 parts by weight (w/w), preferably 0.1-50:0.1 -50: 0.1-50 parts by weight (w/w), more preferably 0.1-10: 0.1-10: 0.1-10 parts by weight (w/w), more preferably 1 - 5:1-5:1-5 parts by weight (w/w), most preferably 1-3:1-3:1-3 parts by weight (w/w) of longan meat, straw book and onji Contains mixtures of each extract.

本発明に開示する用語「抽出物」は、水、Ｃ１－Ｃ４低級アルキルアルコール、例えば、メタノール、エタノール、プロパノール、ブタノール、など、アセトン、酢酸エチル、クロロホルム、ヘキサン、ブチレングリコール、プロピレングリコールまたはグリセリン、好ましくは、水、メタノール、エタノール、より好ましくは、水または水中１０～９０％（ｖ／ｖ）エタノール、最も好ましくは、水または水中２０～８０％（ｖ／ｖ）エタノールから選択される１つ以上の溶媒で抽出することができる抽出物を含む。 The term “extract” disclosed in the present invention includes water, C 1 -C 4 lower alkyl alcohols such as methanol, ethanol, propanol, butanol, etc., acetone, ethyl acetate, chloroform, hexane, butylene glycol, propylene glycol or Glycerin, preferably selected from water, methanol, ethanol, more preferably 10-90% (v/v) ethanol in water or water, most preferably 20-80% (v/v) ethanol in water or water Includes extracts that can be extracted with one or more solvents.

本明細書で開示する用語「炎症性疾患」は、皮膚炎、アトピー性皮膚炎、結膜炎、歯周炎、鼻炎、中耳炎、咽頭痛、扁桃炎、肺炎、胃潰瘍、胃炎、クローン病、大腸炎、痔、痛風、リウマチ熱、狼瘡、線維筋痛症、腱炎、腱鞘炎、腱周囲炎、筋炎、肝炎、膀胱炎、腎炎、シェーグレン症候群、慢性炎症および急性炎症によって引き起こされる掻痒症の群から選択される疾患を含む。 The term "inflammatory disease" disclosed herein includes dermatitis, atopic dermatitis, conjunctivitis, periodontitis, rhinitis, otitis media, sore throat, tonsillitis, pneumonia, stomach ulcer, gastritis, Crohn's disease, colitis, pruritus caused by hemorrhoids, gout, rheumatic fever, lupus, fibromyalgia, tendinitis, tenosynovitis, peritendinitis, myositis, hepatitis, cystitis, nephritis, Sjögren's syndrome, chronic inflammation and acute inflammation including diseases that

本発明に開示する用語「抗リウマチ」 は、あらゆるリウマチを抑制するすべての機序を意味し、これらに限定されない。 The term "anti-rheumatoid arthritis" disclosed in the present invention means, but is not limited to, all mechanisms of suppressing rheumatoid arthritis.

炎症は、病原体、損傷した細胞、または刺激物質などの有害な刺激に対する身体組織の複雑な生物学的反応の一部であり、熱、痛み、発赤、腫れなどの非特異的免疫応答を「炎症反応」と呼ぶ。 Inflammation is part of the complex biological response of the body's tissues to noxious stimuli such as pathogens, damaged cells, or irritants, and refers to nonspecific immune responses such as heat, pain, redness, and swelling. called "reaction".

炎症は、（ａ）有害な刺激に対する身体の初期反応である急性炎症であって、血液からの血漿および白血球（特に顆粒球）の損傷した組織への移動の増加によって達成され、その後、一連の生化学的事像が伝播され、そして局所血管系、免疫系、および損傷した組織内の様々な細胞に関連する炎症反応成熟によって達成される、炎症、および（ｂ）慢性炎症として知られる炎症の長期化により、炎症部位に存在する細胞の種類、例えば、単核細胞の漸進的な変化をもたらし、炎症過程における組織の同時破壊および治癒を特徴とする、炎症として分類することができる。 Inflammation is (a) the body's initial response to noxious stimuli, acute inflammation, which is accompanied by increased migration of plasma and leukocytes (especially granulocytes) from the blood into damaged tissues, followed by a series of Inflammation, known as chronic inflammation, and (b) chronic inflammation, which is accompanied by maturation of the inflammatory response, which is propagated by biochemical events and involves the local vasculature, immune system, and various cells within the injured tissue. Prolongation leads to progressive changes in the types of cells present at the site of inflammation, eg, mononuclear cells, and can be classified as inflammation, characterized by simultaneous tissue destruction and healing in the inflammatory process.

一般に、損傷した細胞のマクロファージは、様々なサイトカインを放出し、Ｔリンパ球を活性化し、リンパ球である肥満細胞は様々なヒスタミンを放出し、内部障壁反応を起こし、感染した細胞の炎症を誘導する。したがって、細胞サイトカインの発現レベルは、炎症反応の活性化（他の様態ら、抗炎症活性）の指標として用いることができる。本発明に開示される「抗炎症活性」は、様々な皮膚炎症に対する抑制活性を意味する。 In general, damaged cells, macrophages, release various cytokines to activate T lymphocytes, and mast cells, which are lymphocytes, release various histamines, initiate an internal barrier reaction, and induce inflammation in infected cells. do. Therefore, expression levels of cellular cytokines can be used as an indicator of activation of inflammatory responses (other modalities, anti-inflammatory activity). "Anti-inflammatory activity" disclosed in the present invention means suppressive activity against various skin inflammations.

サイトカインは、ケモカイン、インターフェロン、インターロイキン、リンホカイン、およびマクロファージ、Ｂリンパ球、Ｔリンパ球、および肥満細胞などの免疫細胞だけでなく、内皮細胞を含む広範囲の細胞によって産生される腫瘍壊死因子、線維芽細胞、および様々な病原体、例えば、ウイルスなどの侵入によって引き起こされる免疫学的な進行を通じて放出される、多様な基質細胞を含むすべての免疫学的物質を意味する。 Cytokines are chemokines, interferons, interleukins, lymphokines, and tumor necrosis factor produced by a wide range of cells, including endothelial cells, as well as immune cells such as macrophages, B lymphocytes, T lymphocytes, and mast cells. Blast cells and all immunological substances, including various stromal cells, released through the immunological process caused by invasion of various pathogens, such as viruses.

一般に、サイトカインは 感染初期に放出されるが、免疫システムが異常に活性化されると、持続的に放出される。一週間以上などの長期間にわたって高レベルのサイトカインが放出された場合を、本発明者らは「サイトカインストーム（ｓｔｏｒｍ）」と呼んでいる。これは自然免疫系がサイトカインと呼ばれるプロ炎症性シグナル送達分子が抑制不能となり、過剰な放出を惹起する、また、免疫細胞が感染部位に極度に大量にホーミングすることで炎症を悪化させ、血管を弛緩させて血管外漏出を起こし、最悪の場合、死に至らしめる、生理的反応である。本発明に開示する用語「サイトカイン発現の抑制活性」は、サイトカインストームの予防、治療または改善として解釈することができる。 In general, cytokines are released early in infection, but are released continuously when the immune system is abnormally activated. When high levels of cytokines are released for an extended period of time, such as a week or more, we refer to this as a "cytokine storm." This is caused by the innate immune system becoming uncontrollable and triggering excessive release of pro-inflammatory signaling molecules called cytokines, and by homing extremely large numbers of immune cells to the site of infection, exacerbating inflammation and reducing blood vessels. It is a physiological response that leads to relaxation, extravasation and, in the worst case, death. The term "cytokine expression suppression activity" disclosed in the present invention can be interpreted as prevention, treatment or amelioration of cytokine storm.

本発明に開示する用語「サイトカイン」は、アトピー性皮膚炎などの皮膚炎に関与する様々なサイトカイン、具体的には、ＴＬＳＰ（胸腺間質リンホポエチン）、コロニー刺激因子（ＣＳＦ）、例えば、ＧＭ－ＣＳＦ（顆粒球－マクロファージコロニー刺激因子）、Ｍ－ＣＳＦ（マクロファージコロニー刺激因子）、Ｇ－ＣＳＦ（顆粒球コロニー刺激因子）など、インターロイキン、例えばインターロイキン－１（ＩＬ－１）、ＩＬ－４、ＩＬ－１０、ＩＬ－１２、ＩＬ－１３、ＩＬ－３１、ＩＬ－３３など、腫瘍壊死因子アルファ（ＴＮＦ－α）、インターフェロンガンマ（ＩＦＮγ）などの群から選択されたサイトカインを含むが、これらに限定されるものではない。 The term "cytokine" disclosed in the present invention includes various cytokines involved in dermatitis such as atopic dermatitis, specifically TLSP (thymic stromal lymphopoietin), colony stimulating factor (CSF), such as GM- CSF (granulocyte-macrophage colony stimulating factor), M-CSF (macrophage colony stimulating factor), G-CSF (granulocyte colony stimulating factor), etc., interleukins such as interleukin-1 (IL-1), IL-4 , IL-10, IL-12, IL-13, IL-31, IL-33, etc., tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), etc. is not limited to

本発明の抽出物は、以下の好ましい実施形態に従って調製することができる。 The extract of the present invention can be prepared according to the following preferred embodiments.

本発明の場合、前記抽出物は、以下のように調製することができる。 For the present invention, said extract can be prepared as follows.

本発明で定義されている用語「竜眼肉、藁本、およびオンジの混合生薬抽出物」は；「竜眼肉、藁本、およびオンジ」をスライスして洗浄し、第１段階の基本抽出物質として使用する段階；０．０１－１００：０．０１－１００：０．０１－１００重量部（ｗ／ｗ）、好ましくは、０．１－５０：０．１－５０：０．１－５０重量部（ｗ／ｗ）、より好ましくは、０．１－１０：０．１－１０：０．１－１０重量部（ｗ／ｗ）、さらに好ましくは、１－５：１－５：１－５重量部（ｗ／ｗ）、最も好ましくは、１－３：１－３：１－３重量部（ｗ／ｗ）範囲の竜眼肉、藁本およびオンジの乾燥重量（ｗ／ｗ）を基準とした混合比でよく混ぜ合わせ、第２段階の混合物質を得る段階；第３段階において、水、Ｃ１－Ｃ４低級アルキルアルコール、例えば、メタノール、エタノール、プロパノール、ブタノール、など、アセトン、酢酸エチル、クロロホルム、ヘキサン、ブチレングリコール、プロピレングリコールまたはグリセリン、好ましくは、水、メタノール、エタノール、より好ましくは、水または水中１０～９０％（ｖ／ｖ）エタノール、最も好ましくは、水または水中２０～８０％（ｖ／ｖ）エタノールからなる群から選択される抽出溶媒１～２０倍体積（ｖ／ｗ）、好ましくは４～８倍体積（ｖ／ｗ）を混合物質に添加する段階；第４段階において、５０℃～１２０℃、好ましくは、約８０℃～１００℃の温度範囲で１～２４時間、好ましくは、２～１２時間の範囲の間、熱水抽出、冷水抽出、還流抽出または超音波抽出、好ましくは、熱水抽出による抽出法で各溶液を抽出する段階；前記抽出過程を繰り返し、各濾液を濾過、凍結乾燥、自然乾燥または熱風乾燥過程を介した乾燥、好ましくは凍結乾燥過程により収集し、本発明の竜眼肉、藁本およびオンジの混合生薬抽出物を得る段階を含む手順によって調製することができる。 The term "longan meat, straw root and onji mixed crude drug extract" defined in the present invention; Stage; w/w), more preferably 0.1-10:0.1-10:0.1-10 parts by weight (w/w), more preferably 1-5:1-5:1-5 parts by weight parts (w/w), most preferably in the range of 1-3:1-3:1-3 parts by weight (w/w) ratio to obtain the second stage mixture; in the third stage, water, C 1 -C 4 lower alkyl alcohols such as methanol, ethanol, propanol, butanol, etc., acetone, ethyl acetate, chloroform , hexane, butylene glycol, propylene glycol or glycerin, preferably water, methanol, ethanol, more preferably 10-90% (v/v) ethanol in water or water, most preferably 20-80% (v/v) in water or water. v/v) adding 1 to 20 volumes (v/w), preferably 4 to 8 volumes (v/w) of an extraction solvent selected from the group consisting of ethanol to the mixed substance; hot water extraction, cold water extraction, reflux extraction or ultrasonic extraction at a temperature range of 50° C. to 120° C., preferably about 80° C. to 100° C., for a period of 1 to 24 hours, preferably 2 to 12 hours; Extracting each solution by an extraction method, preferably by hot water extraction; repeating the extraction process and collecting each filtrate by filtration, freeze drying, air drying or drying via a hot air drying process, preferably a freeze drying process. , a procedure comprising the step of obtaining the mixed herbal extract of longan meat, straw bonito and onji of the present invention.

本発明の別の目的は、上述のように、本発明の竜眼肉、藁本およびオンジの混合生薬抽出物を調製する方法を提供することである。 Another object of the present invention is to provide a method for preparing the mixed herbal extract of Longan, Strawberry and Onji of the present invention as described above.

本発明の別の目的は、皮膚潰瘍を治療および改善するための上記のような方法で調製された竜眼肉、藁本およびオンジの混合生薬抽出物を有効成分として含む経口用医薬組成物を提供することである。 Another object of the present invention is to provide an oral pharmaceutical composition containing as an active ingredient the mixed herbal extract of Longan, Strawberry and Onji prepared by the above method for treating and improving skin ulcers. That is.

本発明のまた別の態様によれば、有効量の竜眼肉、藁本およびオンジの混合生薬抽出物、およびその薬学的に許容される担体を哺乳動物に経口投与する段階を含む、哺乳動物の炎症性疾患を治療または改善する方法が提供される。 According to yet another aspect of the present invention, treating inflammation in a mammal comprising orally administering to the mammal an effective amount of a mixed herbal extract of longan, straw and onji, and a pharmaceutically acceptable carrier thereof. Methods of treating or ameliorating sexually transmitted diseases are provided.

本発明の別の態様によれば、ヒトを含む哺乳動物の炎症性疾患を治療または改善するために使用される経口製剤を調製するための竜眼肉、藁本およびオンジの混合生薬抽出物の有効成分としての使用もまた提供される。 According to another aspect of the present invention, the active ingredient of the mixed herbal extract of longan, straw and onji for preparing an oral formulation used for treating or ameliorating inflammatory diseases in mammals, including humans Use as is also provided.

本発明のまた別の目的は、炎症性疾患の予防および治療のための上記のような方法により得られた上記生薬抽出物を有効成分として含有する医薬組成物または健康機能性食品を提供することである。 Still another object of the present invention is to provide a pharmaceutical composition or health functional food containing, as an active ingredient, the crude drug extract obtained by the above method for the prevention and treatment of inflammatory diseases. is.

本発明者らは、炎症に関与するサイトカイン（ＲＰＬＰＯ、ＴＳＬＰ、ＧＭ－ＣＳＦおよびＩＬ－１β）の発現抑制試験（実験例１）；ＨＴ－２９およびＴＨＰ－１細胞の細胞生存率試験（ｉｎ ｖｉｔｒｏ、実験例２）；ＴＨＰ－１細胞における抗炎症活性（ｉｎ ｖｉｔｒｏ、実験例３）；オートファジー活性抑制効果（ｉｎ ｖｉｔｒｏ、実験例４）などのｉｎ ｖｉｔｒｏ実験だけでなく、関節炎誘発ラット動物モデルを用いた関節炎抑制効果（ｉｎ ｖｉｖｏ、実験例５）と同様のｉｎ ｖｉｖｏ実験を行うことにより、本発明の組成物の抗炎症／抗リウマチ効果が強力であることが立証された。したがって、本発明の混合抽出物が、経口用医薬組成物の形態として炎症性疾患および関節炎疾患の改善または治療に非常に有用であることを確認した。 The present inventors performed an expression suppression test of cytokines (RPLPO, TSLP, GM-CSF and IL-1β) involved in inflammation (Experimental Example 1); a cell viability test of HT-29 and THP-1 cells (in vitro , Experimental Example 2); anti-inflammatory activity in THP-1 cells (in vitro, Experimental Example 3); autophagy activity inhibitory effect (in vitro, Experimental Example 4), as well as arthritis-induced rat animal models It was proved that the anti-inflammatory/anti-rheumatic effect of the composition of the present invention is strong by performing the same in vivo experiment as the arthritis inhibitory effect using (in vivo, Experimental Example 5). Therefore, it was confirmed that the mixed extract of the present invention, in the form of an oral pharmaceutical composition, is very useful for ameliorating or treating inflammatory diseases and arthritic diseases.

上記目的の疾患を治療するための医薬組成物は、組成物の総重量基準で上記本発明の生薬抽出物を約０．０１～９９ｗ／ｗ％含有することができる。 A pharmaceutical composition for treating the above-mentioned diseases of interest may contain about 0.01-99 w/w% of the herbal extract of the present invention, based on the total weight of the composition.

しかし、上記組成物の量および各成分は、患者の状態、患者の疾患の進行、病状の種類などによって変わり得る。 However, the amount and each component of the composition may vary depending on the patient's condition, the patient's disease progression, type of medical condition, and the like.

本発明の組成物は、使用方法によって従来の担体、アジュバントまたは希釈剤をさらに含むことができる。 The compositions of the invention can further contain conventional carriers, adjuvants or diluents depending on the method of use.

本発明による生薬組成物は、粉末、顆粒、錠剤、カプセル、懸濁液、エマルジョン、シロップ、エアロゾルなどの経口投与形態；局所製剤；または注射溶液として剤形化することができる。本発明による生薬組成物は、薬学的に許容される担体、アジュバントまたは希釈剤、例えば、ラクトース、デキストロース、スクロース、ソルビトール、マンニトール、キシリトール、エリスリトール、マルチトール、デンプン、アカシアゴム、アルギン酸、ゼラチン、リン酸カルシウム、ケイ酸カルシウム、セルロース、メチルセルロース、微結晶セルロース、ポリビニルピロリドン、水、ヒドロキシ安息香酸メチル、ヒドロキシ安息香酸プロピル、ステアリン酸マグネシウムおよび鉱物油を含む医薬組成物として提供されることができる。剤形は、充填剤、増量剤、結合剤、湿潤剤、崩壊剤、界面活性剤、希釈剤などの賦形剤をさらに含むことができる。固体経口投与形態は、錠剤、丸剤、散剤、顆粒剤、カプセル剤などを含み、固体経口投与形態は、生薬抽出物にデンプン、炭酸カルシウム、スクロース、ラクトースまたはゼラチンなどの少なくとも１つの賦形剤を添加することによって調製される。ステアリン酸マグネシウムまたはタルクなどの潤滑剤を使用することができる。水性経口投与形態は、懸濁液、経口溶液、エマルジョン、シロップを含み、水性経口投与形態は、湿潤剤、甘味料、香味料、防腐剤だけでなく、水、流動パラフィンなどのあらゆる賦形剤を含み得る。非経口投与形態は、滅菌水溶液、非水性溶媒、懸濁液、エマルジョン、凍結乾燥製剤、坐剤などを含む。担体の適切な例としては、プロピレングリコール、ポリエチレングリコール、オリーブ油などの植物性油、エチルオレートなどの注射可能なエステルが含まれる。坐剤の基剤としては、ウィテプソル（ｗｉｔｅｐｓｏｌ）、マクロゴール（ｍａｃｒｏｇｏｌ）、ツイン６１（ｔｗｅｅｎ ６１）、カカオバター、ラウリン（ｌａｕｒｉｎ）、グリセロゼラチンなどが挙げられるが、これらに限定されるものではない。 The herbal composition according to the present invention can be formulated as oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols; topical formulations; or injection solutions. The herbal composition according to the present invention contains a pharmaceutically acceptable carrier, adjuvant or diluent such as lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginic acid, gelatin, calcium phosphate. , calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, magnesium stearate and mineral oil. The dosage form can further comprise excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, diluents and the like. Solid oral dosage forms include tablets, pills, powders, granules, capsules, etc. Solid oral dosage forms contain at least one excipient such as starch, calcium carbonate, sucrose, lactose or gelatin in herbal extracts. is prepared by adding Lubricating agents such as magnesium stearate or talc can be used. Aqueous oral dosage forms include suspensions, oral solutions, emulsions, syrups, and aqueous oral dosage forms may contain any excipients such as water, liquid paraffin, etc., as well as wetting agents, sweeteners, flavoring agents, and preservatives. can include Parenteral dosage forms include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, suppositories, and the like. Suitable examples of carriers include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include, but are not limited to, witepsol, macrogol, tween 61, cocoa butter, laurin, glycerogelatin, and the like. .

本発明の組成物の好ましい用量は、対象体の状態および体重、重症度、薬物形態、投与経路および期間によって変わり、当業者によって選択され得る。しかし、好ましい効果を得るためには、一般に本発明の本組成物を０．０１ｍｇ／ｋｇ～１０ｇ／ｋｇ、好ましくは、１ｍｇ／ｋｇ～１ｇ／ｋｇ（重量／日） の範囲の量で投与することが推奨される。用量は、１日当たり１回または複数回の用量で投与することができる。 A preferred dose of the composition of the present invention varies according to the subject's condition and weight, severity, drug form, administration route and duration, and can be selected by those skilled in the art. Generally, however, the compositions of the invention are administered in amounts ranging from 0.01 mg/kg to 10 g/kg, preferably from 1 mg/kg to 1 g/kg (weight/day) to obtain the desired effect. recommended. Doses can be administered in one or more doses per day.

本発明の医薬組成物は、様々な経路を介して哺乳動物（ラット、マウス、家畜またはヒト）などの対象体の動物に投与することができる。すべての投与方式が考えられ、例えば、投与は経口、直腸、または静脈内注射によって行うことができる。 The pharmaceutical composition of the present invention can be administered to an animal subject such as a mammal (rat, mouse, livestock or human) via various routes. All modes of administration are contemplated, for example administration can be by oral, rectal or intravenous injection.

本発明の一態様によれば、本発明は、炎症性疾患の予防または改善のための竜眼肉（Ｌｏｎｇａｎａｅ Ａｒｉｌｌｕｓ）、藁本（Ｌｉｇｕｓｔｉｃｉ Ｔｅｎｕｉｓｓｉｍｉ Ｒｈｉｚｏｍａ）およびオンジ（Ｐｏｌｙｇａｌａｅ ｒａｄｉｘ）の混合生薬抽出物を有効成分として含む健康機能食品を提供する。 According to one aspect of the present invention, the present invention uses a mixed crude drug extract of Longanae Arillus, Ligustici Tenuissimi Rhizoma and Polygalae radix for the prevention or improvement of inflammatory diseases as an active ingredient. Provide health functional food containing as.

本明細書に開示する用語「健康機能食品」は、ヒトまたは哺乳動物の目的とする疾患を予防または改善するために従来の食品に本発明の抽出物を添加することにより、物理的機能性または生理的機能性などといった機能性が強化された機能性食品として、韓国健康機能食品法６７２７条によって規定されている。 The term "food with health claims" disclosed herein refers to the physical functionality or It is stipulated by Article 6727 of the Korean Health Functional Food Act as a functional food with enhanced functionality such as physiological functionality.

前記目的の疾患を予防および改善するための健康機能食品組成物は、組成物の総重量基準で約０．０１～９５ｗ／ｗ％、好ましくは１～８０ｗ／ｗ％の前記本発明の生薬組成物を含有することができる。 The functional health food composition for preventing and ameliorating the target disease contains about 0.01 to 95 w/w%, preferably 1 to 80 w/w% of the crude drug composition of the present invention, based on the total weight of the composition. can contain objects.

また、本発明の本抽出物は、炎症性疾患の予防または改善のための様々な健康機能食品および健康補助食品の製造時、主成分または添加剤および補助剤として使用することができる。 In addition, the present extract of the present invention can be used as a main ingredient or additive and adjuvant in the production of various health functional foods and health supplements for the prevention or improvement of inflammatory diseases.

本発明の健康機能食品は、散剤、顆粒剤、錠剤、カプセル剤、丸剤、懸濁剤、乳剤、シロップなどの薬学的に許容される投与形態；またはティーバッグ、浸出茶、健康飲料形態などの健康機能食品形態で製造および加工することができる。 The health functional food of the present invention is in pharmaceutically acceptable dosage forms such as powders, granules, tablets, capsules, pills, suspensions, emulsions, syrups; or tea bags, infused teas, health drink forms, etc. can be manufactured and processed in the form of functional health food.

本発明のまた別の目的は、炎症性疾患の予防または改善のための竜眼肉（Ｌｏｎｇａｎａｅ Ａｒｉｌｌｕｓ）、藁本（Ｌｉｇｕｓｔｉｃｉ Ｔｅｎｕｉｓｓｉｍｉ Ｒｈｉｚｏｍａ）およびオンジ（Ｐｏｌｙｇａｌａｅ ｒａｄｉｘ）の混合生薬抽出物を有効成分または主成分として含む健康補助食品を提供することである。 Still another object of the present invention is to use a mixed crude drug extract of Longanae Arillus, Ligustici Tenuissimi Rhizoma and Polygalae radix as an active ingredient or main ingredient for the prevention or improvement of inflammatory diseases. to provide a health supplement containing

上述の用語「主成分」とは、前記健康補助食品が組成物の総重量基準で約３０～９９（ｗ／ｗ％）、好ましくは５０～９９（ｗ／ｗ％）、より好ましくは７０～９９（ｗ／ｗ）の本発明の抽出物を含むことを意味する。 The term "main ingredient" as mentioned above means that said dietary supplement contains about 30-99 (w/w%), preferably 50-99 (w/w%), more preferably 70-99% (w/w%) based on the total weight of the composition. It is meant to contain 99 (w/w) of the extract of the present invention.

本発明の混合生薬抽出物を健康機能飲料組成物の成分として使用する場合、健康機能性飲料組成物は、従来の飲料組成物と同様に制限なく香味剤または天然炭水化物などの他の成分を含むことができる。天然炭水化物としては、例えば、グルコース、フルクトースなどの単糖類；マルトース、スクロースなどの二糖類；および多糖類、例えば、デキストリン、シクロデキストリンなどの糖、および糖アルコール、例えば、キシリトール、ソルビトール、エリスリトールが含まれる。健康機能性飲料組成物には、天然香料（タウマチン、ステビア抽出物（レバウジオサイドＡ、グリシリジンなど））および合成着香料（サッカリン、アスパルテームなど）を添加することができる。天然炭水化物の量は、一般に、本組成物１００ｍｌ当たり約１～２０ｇ、好ましくは約５～１２ｇの範囲である。 When the mixed crude drug extract of the present invention is used as a component of a health functional beverage composition, the health functional beverage composition contains without limitation other ingredients such as flavoring agents or natural carbohydrates, like conventional beverage compositions. be able to. Natural carbohydrates include, for example, monosaccharides such as glucose, fructose; disaccharides such as maltose, sucrose; be Natural flavors (thaumatin, stevia extracts (rebaudioside A, glycyrrhizin, etc.)) and synthetic flavors (saccharin, aspartame, etc.) can be added to the health functional beverage composition. The amount of natural carbohydrates generally ranges from about 1-20 g, preferably from about 5-12 g, per 100 ml of the composition.

本発明の混合生薬抽出物を健康食品の食品添加物として使用する場合、混合生薬抽出物をそのまま添加してもよく、一般工程に従って他の食品成分と併用してもよい。食品の例としては、目的とする疾患の予防または改善のために、肉製品、ソーセージ、パン、チョコレート、キャンディ、スナック、クラッカー、ビスケット、ピザ、ラーメン、麺類、チューインガム、アイスクリームなどの乳製品、スープ、飲料（ｂｅｖｅｒａｇｅ）、お茶、飲料（ｄｒｉｎｋ）、酒類、ビタミン複合体などが含まれるが、これらに限定されるものではない。 When the mixed crude drug extract of the present invention is used as a food additive for health foods, the mixed crude drug extract may be added as it is, or may be used in combination with other food ingredients according to general processes. Examples of foods include meat products, sausages, bread, chocolate, candy, snacks, crackers, biscuits, pizza, ramen, noodles, chewing gum, dairy products such as ice cream, Including, but not limited to, soups, beverages, teas, drinks, alcoholic beverages, vitamin complexes and the like.

上記組成物以外の他の成分としては、各種栄養素、ビタミン、ミネラル又は電解質、合成香料、着色剤およびチーズの場合、改良剤、チョコレート等、ペクチン酸およびその塩、アルギン酸およびその塩、有機酸、保護コロイド接着剤、ｐＨ調整剤、安定化剤、保存剤、グリセリン、アルコール、炭酸飲料に使用される炭化剤などがある。上記成分以外の他の成分は、天然フルーツジュース製造用フルーツジュース、フルーツジュース飲料および野菜飲料であってもよく、これらの成分は単独でまたは組み合わせて使用することができる。成分の割合はそれほど重要ではないが、一般的には存在する組成物１００ｗ／ｗ％当たり約０～２０ｗ／ｗ％の範囲である。 Other ingredients other than the above composition include various nutrients, vitamins, minerals or electrolytes, synthetic flavors, coloring agents and cheese improvers, chocolate and the like, pectic acid and its salts, alginic acid and its salts, organic acids, These include protective colloid adhesives, pH adjusters, stabilizers, preservatives, glycerin, alcohol, and carbonizing agents used in carbonated beverages. Ingredients other than those mentioned above may be fruit juices, fruit juice beverages and vegetable beverages for the production of natural fruit juices, and these ingredients can be used alone or in combination. The proportions of the ingredients are not critical, but generally range from about 0-20% w/w per 100% w/w of the composition present.

また、上記の抽出物は、目的とする障害の予防および改善のために食品または飲料に添加することができる。健康機能食品または健康補助食品としての食品または飲料における上記抽出物の含有量は、一般に、健康機能性食品組成物用食品の総重量の約０．０１～１５ｗ／ｗ％の範囲であってもよい。また、本発明の抽出物は、健康飲料組成物１００ｍｌ当たり０．０２～５ｇ、好ましくは０．３～１ｇを添加することができる。 Also, the above extracts can be added to foods or beverages for the purpose of preventing and ameliorating disorders. The content of the extract in the food or beverage as a health functional food or health supplement is generally in the range of about 0.01 to 15 w/w% of the total weight of the food for health functional food composition. good. Also, the extract of the present invention can be added in an amount of 0.02-5 g, preferably 0.3-1 g, per 100 ml of the health drink composition.

本発明の精神または範囲から逸脱することなく、本発明の組成物、用途および製剤に様々な変更および変形を行うことができることは当業者にとって自明なことであろう。 It will be apparent to those skilled in the art that various modifications and variations can be made in the compositions, uses and formulations of the present invention without departing from the spirit or scope of the invention.

本発明は、以下の実施例によってより具体的に説明される。しかし、本発明はいかなる方法でもこれらの実施形態に限定されないものであることを理解すべきである。 The present invention is more specifically illustrated by the following examples. However, it should be understood that the invention is not in any way limited to these embodiments.

以下の実施例および実験例は、本発明の範囲を限定することなく本発明をさらに例示するためのものである。 The following examples and experimental examples are intended to further illustrate the invention without limiting its scope.

実施例１．本発明の混合抽出物（１）の調製
乾燥竜眼肉（Ｌｏｎｇａｎａｅ Ａｒｉｌｌｕｓ）（Ｂｕｙｏｕｎｇ Ｙａｋｕｐ Ｃｏ．Ｌｔｄ．）２０ｇ、乾燥藁本（Ｌｉｇｕｓｔｉｃｉ Ｔｅｎｕｉｓｓｉｍｉ Ｒｈｉｚｏｍａ）（Ｂｕｙｏｕｎｇ Ｙａｋｕｐ Ｃｏ．Ｌｔｄ．）２０ｇおよび乾燥オンジ（Ｐｏｌｙｇａｌａｅ ｒａｄｉｘ）（Ｂｕｙｏｕｎｇ Ｙａｋｕｐ Ｃｏ．Ｌｔｄ．）２０ｇを小片に切断した後、６倍体積（ｖ／ｗ）の２０％エタノール水溶液と混合し、その混合物を９０±５℃で３日間還流抽出した。抽出物をろ紙（孔径１０μｍ未満）を通して濾過させ、残渣を除去した後、残りの残渣を４倍体積（ｖ／ｗ）の２０％エタノール水溶液でさらに２回抽出し、抽出物をろ紙（孔径、１０μｍ未満）を通して濾過した。 Example 1. Preparation of the mixed extract (1) of the present invention 20 g of dried Longanae Arillus (Buyoung Yakup Co. Ltd.), 20 g of dried Ligustici Tenuissimi Rhizoma (Buyoung Yakup Co. Ltd.) and 20 g of dried Onji (Polygalae) radix ) (Buyoung Yakup Co. Ltd.) was cut into small pieces, mixed with 6 volumes (v/w) of 20% aqueous ethanol solution, and the mixture was reflux extracted at 90±5° C. for 3 days. After the extract was filtered through filter paper (pore size less than 10 μm) to remove the residue, the remaining residue was further extracted twice with four volumes (v/w) of 20% aqueous ethanol solution, and the extract was filtered through filter paper (pore size, less than 10 μm).

収集した抽出物を一緒に混合し、真空下で濃縮し（１６－２１ブリックス）濃縮抽出物を得た。濃縮した抽出物を凍結乾燥過程により乾燥させ、粉砕し（５０メッシュ未満）、本発明の混合抽出物（１）（以下、「ＷＩＮ－１００１Ｘ」と表す）２０．５ｇを得た（乾燥基準粉末、収率３３．４％）。 The collected extracts were mixed together and concentrated under vacuum (16-21 Brix) to obtain a concentrated extract. The concentrated extract was dried by a freeze-drying process and ground (less than 50 mesh) to obtain 20.5 g of the mixed extract of the present invention (1) (hereinafter referred to as "WIN-1001X") (dry basis powder , yield 33.4%).

実施例２－６．本発明の混合抽出物（２）－（６）の調製
実施例１に開示されたものとは異なる混合比および異なる溶媒を用いたことを除いては、全ての手順が実施例１と同様であり、竜眼肉（ＬＡ）、藁本（ＬＴ）およびオンジ（ＰＲ）の様々な本発明の混合抽出物、すなわち、本発明の混合抽出物（２）ないし本発明の混合抽出物（６）を得た。これを以下の実験にて試験試料として使用する。 Example 2-6. Preparation of Mixed Extracts (2)-(6) of the Present Invention All procedures were the same as in Example 1, except that different mixing ratios and different solvents were used than those disclosed in Example 1. There are various mixed extracts of the present invention of longan (LA), straw (LT) and onji (PR), that is, the mixed extract (2) of the present invention to the mixed extract (6) of the present invention. rice field. It is used as a test sample in the following experiments.

Figure 2023519549000001
Figure 2023519549000001

実験例１．サイトカイン発現に対する抑制効果（ｉｎ ｖｉｔｒｏ）
本発明の抽出物の抗炎症活性を決定するために、文献（Ｊｅｏｎｇ ｅｔ ａｌ．，２０１９，Ｊ．Ｉｎｖｅｓｔ．Ｄｅｒｍａｔｏｌ．，Ｍａｙ；１３９ （５）：ｐｐ１０９８－１１０９）に記載された手順に従って、ＨａＣａＴ細胞を用いた以下のサイトカイン発現抑制試験を行った。 Experimental example 1. Suppressive effect on cytokine expression (in vitro)
To determine the anti-inflammatory activity of the extract of the present invention, HaCaT The following cytokine expression suppression test using cells was performed.

１０％ウシ胎児血清、１００単位／ｍｌのペニシリン、１００μｇ／ｍｌのストレプトマイシン（Ｄ６４２９、Ｓｉｇｍａ－Ａｌｄｒｉｃｈ Ｃｏ．Ｌｔｄ）を含有するＤＭＥＭ培地にＨａＣａＴ細胞（ヒト表皮角化細胞、３００４９３、ＣＬＳ）を接種し、最適湿度（８５～９５％）および５％のＣＯ２雰囲気を維持しながらインキュベーター（ＨＥＲＡ ｃｅｌｌ １５０ｉ， Ｔｈｅｒｍｏ Ｆｉｓｈｅｒ Ｓｃｉｅｎｔｉｆｉｃ Ｃｏ． Ｌｔｄ．）でインキュベートした。 HaCaT cells (human epidermal keratinocytes, 300493, CLS) were inoculated into DMEM medium containing 10% fetal bovine serum, 100 units/ml penicillin, and 100 μg/ml streptomycin (D6429, Sigma-Aldrich Co. Ltd.). , in an incubator (HERA cell 150i, Thermo Fisher Scientific Co. Ltd.) while maintaining an optimal humidity (85-95%) and 5% CO 2 atmosphere.

遺伝子発現試験を行うために、インキュベートした細胞を１２ウェルに移し、５０ｎｇ／ｍｌのＴＮＦアルファ（ＲＣ２１４－１２， Ｂｉｏｂａｓｉｃ Ｃｏ． Ｌｔｄ）をそれと共に１時間処理し、炎症反応を誘導した。デキサメタゾン（２００ｎＭ、陽性対照群、「ＤＥＸ」、Ｄ４９０２,Ｓｉｇｍａ－Ａｌｄｒｉｃｈ Ｃｏ．Ｌｔｄ．）および蒸留水（陰性対照群、「ＤＩＷ」）を比較対照群として使用した。 To perform gene expression studies, incubated cells were transferred to 12 wells and treated with 50 ng/ml TNF alpha (RC214-12, Biobasic Co. Ltd) for 1 hour to induce inflammatory response. Dexamethasone (200 nM, positive control group, "DEX", D4902, Sigma-Aldrich Co. Ltd.) and distilled water (negative control group, "DIW") were used as comparative controls.

炎症誘発１時間後、実施例で調製した本発明の抽出物１μｇ／ｍｌを同じ培地で処理し、１時間インキュベートした。インキュベーションした後、細胞からＲＮＡ（ＦＡＴＲＲ－００１、Ｆａｖｏｒｇｅｎ）を抽出し、ｃＤＮＡ合成キット（ＲＲＯ３６Ａ、ＴＡＫＡＲＡ）を用いてＲＮＡからｃＤＮＡを合成した。合成されたｃＤＮＡとＳｙｂｒｇｒｅｅｎキット（ＲＴ５００Ｍ、Ｅｎｚｙｎｏｍｉｃｓ）を用いて重合反応を行った後、表２に示すような皮膚炎症に関与する様々なサイトカインに対するプライマー（ＲＰＬＰＯ、ＴＳＬＰ、ＧＭ－ＣＳＦ、およびＩＬ－１β）を用いてリアルタイムＰＣＲを行った。 One hour after induction of inflammation, 1 μg/ml of the extract of the present invention prepared in the example was treated with the same medium and incubated for 1 hour. After incubation, RNA (FATRR-001, Favorgen) was extracted from the cells, and cDNA was synthesized from the RNA using a cDNA synthesis kit (RRO36A, TAKARA). After performing a polymerization reaction using the synthesized cDNA and a Sybrgreen kit (RT500M, Enzynomics), primers (RPLPO, TSLP, GM-CSF, and IL- 1β) was used to perform real-time PCR.

Figure 2023519549000002
Figure 2023519549000002

ＲＴ－ＰＣＲの定量的結果を示す表３から分かるように、本発明の抽出物で処理された試験試料群は、蒸留水（ＤＩＷ）で処理した陰性対照群に比べて炎症に関与する様々なサイトカインの発現レベルが大幅に抑制されており、炎症に関与する様々なサイトカインの発現に対する試験試料の抑制活性は、デキサメタゾン（ＤＥＸ）で処理した陽性対照群と同等であることが確認された。 As can be seen from Table 3, which shows the quantitative results of RT-PCR, the test sample group treated with the extract of the present invention exhibited various inflammation-related effects compared to the negative control group treated with distilled water (DIW). It was confirmed that the expression levels of cytokines were greatly suppressed, and the inhibitory activity of the test samples on the expression of various cytokines involved in inflammation was comparable to that of the positive control group treated with dexamethasone (DEX).

したがって、実施例１～６で調製された各種の本発明の混合抽出物は、炎症に対する強力な抑制効果があることが確認された。 Therefore, it was confirmed that various mixed extracts of the present invention prepared in Examples 1 to 6 have a strong inhibitory effect on inflammation.

Figure 2023519549000003
Figure 2023519549000003

実験例２：ＨＴ－２９およびＴＨＰ－１細胞に対する細胞生存率試験（ｉｎ ｖｉｔｒｏ）
ＨＴ－２９細胞およびＴＨＰ－１細胞に対する本発明の抽出物の細胞毒性を確認するために、ＨＴ－２９細胞およびＴＨＰ－１細胞を用いた以下の細胞生存率は、当技術分野における既知の手順に従った。 Experimental Example 2: Cell viability test for HT-29 and THP-1 cells (in vitro)
To confirm the cytotoxicity of the extracts of the present invention against HT-29 and THP-1 cells, the following cell viability assays using HT-29 and THP-1 cells were performed using procedures known in the art. followed.

２－１．手順
ＨＴ－２９細胞（ヒト結腸上皮細胞、韓国細胞株バンク、韓国細胞株研究財団、ソウル市鍾路区大学路１０１、０３０８０、韓国）を１０％小胎児血清と１％ペニシリン－ストレプトマイシン溶液を含有するＤＭＥＭ培地に接種し、ＴＨＰ－１細胞（ヒト単核球細胞、韓国細胞株バンク、韓国細胞株研究財団、ソウル市鍾路区大学路１０１、０３０８０、韓国）を１０％小胎児血清および１％ペニシリン－ストレプトマイシン溶液を含有するＲＰＭＩ培地に接種し、インキュベートした。 2-1. Procedure HT-29 cells (human colonic epithelial cells, Korea Cell Line Bank, Korea Cell Line Research Foundation, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea) containing 10% small fetal serum and 1% penicillin-streptomycin solution Inoculated into DMEM medium, THP-1 cells (human mononuclear cells, Korea Cell Line Bank, Korea Cell Line Research Foundation, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea) were added with 10% small fetal serum and 1% penicillin. - Seeded and incubated in RPMI medium containing streptomycin solution.

２５、５０、１００、２５０、５００および１０００μｇ／ｍＬの試験試料をＨＴ－２９細胞およびＴＨＰ－１細胞に添加した。インキュベーション２４時間後にＣＣＫ－８（細胞計数キット－８、Ｄｏｊｉｎｄｏ Ｍｏｌｅｃｕｌａｒ Ｔｅｃｈｎｏｌｏｇｉｅｓ， Ｉｎｃ．）を添加し、４５０ｎｍでの吸光度（光学密度）を測定し、細胞生存率を測定した。 Test samples at 25, 50, 100, 250, 500 and 1000 μg/mL were added to HT-29 and THP-1 cells. After 24 hours of incubation, CCK-8 (cell counting kit-8, Dojindo Molecular Technologies, Inc.) was added and absorbance (optical density) at 450 nm was measured to measure cell viability.

２－２．試験結果
表４に示すように、ＨＴ－２９細胞において本発明の抽出物（２５～１０００μｇ／ｍＬ）で処理した試験試料群の細胞生存率が培地のみで処理された陰性対照群と同様の細胞生存率を示しており、ＴＨＰ－１細胞では、５００および１０００μｇ／ｍＬ濃度でそれぞれ９０．５％および２６．５％を示し、陰性対照群と多少の差を示すことが確認され、５００μｇ／ｍＬ未満の試験試料を以下の試験に適用した。 2-2. Test results As shown in Table 4, the cell viability of the test sample group treated with the extract of the present invention (25-1000 μg/mL) in HT-29 cells was similar to that of the negative control group treated with medium alone. It was confirmed that the survival rate of THP-1 cells was 90.5% and 26.5% at concentrations of 500 and 1000 μg/mL, respectively, showing a slight difference from the negative control group, and 500 μg/mL. Less test samples were applied for the following tests.

Figure 2023519549000004
Figure 2023519549000004

実験例３．ＴＨＰ－１細胞における抗炎症活性（ｉｎ ｖｉｔｒｏ）
本発明の抽出物の抗炎症活性を決定するために、ＴＨＰ－１細胞を用いた以下のプロ炎症性サイトカインレベルの抑制試験を、当技術分野における既知の手順に従って行った。 Experimental example 3. Anti-inflammatory activity in THP-1 cells (in vitro)
To determine the anti-inflammatory activity of the extracts of the present invention, the following pro-inflammatory cytokine level inhibition test using THP-1 cells was performed according to procedures known in the art.

３－１．ＩＬ－１ベータ数値の測定
３－１－１．試験手順
１０、２０、５０、１００、および５００μｇ／ｍＬ脂質多糖類類（ＬＰＳ）をヒト単核球細胞株（ＴＨＰ－１細胞韓国細胞株バンク、韓国細胞株研究財団、ソウル鍾路区大学路１０１、０３０８０、韓国）に添加し、炎症モデルを作製した。 3-1. Measurement of IL-1 beta levels
3-1-1. Test procedure 10, 20, 50, 100, and 500 μg/mL lipid polysaccharide (LPS) was added to a human mononuclear cell line (THP-1 cell line Korean Cell Line Bank, Korea Cell Line Research Foundation, 101 Daehak-ro, Jongno-gu, Seoul). , 03080, Korea) to prepare an inflammation model.

ＬＰＳ処理２４時間後、採取した細胞上清液中の炎症性サイトカインであるＩＬ－１ベータの数値を測定した。 Twenty-four hours after LPS treatment, the levels of IL-1beta, an inflammatory cytokine, were measured in the collected cell supernatant.

また、ＴＨＰ－１細胞において、１０、２５、５０、および１００μｇ／ｍＬの試験試料を４時間処理した後、これでＬＰＳを処理し、試験試料の抗炎症効果を確認した。 Also, THP-1 cells were treated with test samples at 10, 25, 50, and 100 μg/mL for 4 hours and then treated with LPS to confirm the anti-inflammatory effects of the test samples.

ＬＰＳ処理２４時間後、ＥＬＩＳＡリーダー（ＩＬ－１ベータ／ＩＬ－１Ｆ２ ＩＬ－１Ｆ２ Ｄｕｏ ｓｅｔ ＥＬＩＳＡ， Ｒ＆Ｄ Ｓｙｓｔｅｍｓ）を用いてプロ炎症性サイトカインであるＩＬ－１ベータの数値を測定した。 Twenty-four hours after LPS treatment, levels of IL-1beta, a pro-inflammatory cytokine, were measured using an ELISA reader (IL-1beta/IL-1F2 IL-1F2 Duo set ELISA, R&D Systems).

３－１－２．試験結果
表５に示すように、実施例で調製された試験試料は、ＬＰＳを用量依存的に増加させながら増加したＩＬ－１ベータの数値を大幅に減少させたことが確認できた。 3-1-2. As shown in Table 5 of the test results , it was confirmed that the test samples prepared in Examples significantly reduced the increased IL-1 beta level while increasing LPS in a dose-dependent manner.

したがって、実施例で調製された本発明の混合抽出物は、炎症反応に対する強力な抑制効果を有することが確認された。 Therefore, it was confirmed that the mixed extract of the present invention prepared in Examples has a strong inhibitory effect on inflammatory reactions.

Figure 2023519549000005
Figure 2023519549000005

３－２．ＩＬ－１０の数値測定
３－２－１．試験手順
１０、２０、５０、１００、および５００μｇ／ｍＬの脂質多糖類（ＬＰＳ）をヒト単核球細胞株（ＴＨＰ－１細胞韓国細胞株バンク、韓国細胞株研究財団、ソウル鍾路区大学路１０１、０３０８０、韓国）に添加し、炎症モデルを作製した。 3-2. Numerical measurements of IL-10
3-2-1. Test Procedure 10, 20, 50, 100, and 500 μg/mL of lipid polysaccharide (LPS) were added to a human mononuclear cell line (THP-1 cell line), Korea Cell Line Bank, Korea Cell Line Research Foundation, 101 Daehak-ro, Jongno-gu, Seoul. , 03080, Korea) to prepare an inflammation model.

ＬＰＳ処理２４時間後、採取した細胞上清液中の炎症性サイトカインであるＩＬ－１０の数値を測定した。 Twenty-four hours after LPS treatment, the amount of IL-10, an inflammatory cytokine, was measured in the collected cell supernatant.

また、ＴＨＰ－１細胞において、１０、２５、５０、および１００μｇ／ｍＬの試験試料を４時間処理した後、これでＬＰＳを処理し、試験試料の抗炎症効果を確認した。 Also, THP-1 cells were treated with test samples at 10, 25, 50, and 100 μg/mL for 4 hours and then treated with LPS to confirm the anti-inflammatory effects of the test samples.

ＬＰＳ処理２４時間後、ＥＬＩＳＡリーダー（ＩＬ－１０、Ｄｕｏｓｅｔ ＥＬＩＳＡ、Ｒ＆Ｄ Ｓｙｓｔｅｍｓ）を用いてプロ炎症性サイトカインであるＩＬ－１０の数値を測定した。 Twenty-four hours after LPS treatment, levels of IL-10, a pro-inflammatory cytokine, were measured using an ELISA reader (IL-10, Duoset ELISA, R&D Systems).

３－２－２．試験結果
表６に示すように、実施例で調製された試験試料は、ＬＰＳを用量依存的に増加させながら増加したＩＬ－１０の数値を大幅に減少させることが確認できた。 3-2-2. As shown in Table 6 of the test results , it was confirmed that the test samples prepared in Examples significantly reduced the increased IL-10 level while increasing LPS in a dose-dependent manner.

したがって、実施例で調製された本発明の混合抽出物は、炎症反応に対する強力な抑制効果を有することが確認された。 Therefore, it was confirmed that the mixed extract of the present invention prepared in Examples has a strong inhibitory effect on inflammatory reactions.

Figure 2023519549000006
Figure 2023519549000006

実験例４．オートファジー活性抑制効果（ｉｎ ｖｉｔｒｏ）
本発明の抽出物が免疫細胞における炎症性因子の発現に及ぼす効果を測定するために、ＴＨＰ－１細胞を用いた以下の試験を、当技術分野における既知の手順に従って行った。 Experimental example 4. Autophagy activity inhibitory effect (in vitro)
To determine the effect of the extracts of the present invention on the expression of inflammatory factors in immune cells, the following tests using THP-1 cells were performed according to procedures known in the art.

４－１．試験手順
抗炎症活性とオートファジー経路の相関関係を確認するために、１０、２０、５０、１００、および５００μｇ／ｍＬの脂質多糖類（ＬＰＳ）をヒト単核球細胞株（ＴＨＰ－１細胞韓国細胞株バンク、韓国細胞主研究財団、ソウル鍾路区大学路１０１、０３０８０、韓国）に添加し、炎症モデルを作製した。 4-1. Test Procedures To confirm the correlation between anti-inflammatory activity and autophagic pathways, 10, 20, 50, 100, and 500 μg/mL of lipid polysaccharide (LPS) were added to a human mononuclear cell line (THP-1 cells from Korea). Cell Line Bank, Korea Cell Research Foundation, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea) to prepare an inflammation model.

１０、２５、５０、および１００μｇ／ｍＬの試験試料を処理した後、２０および１００μｇ／ｍＬの脂質多糖類（ＬＰＳ）を添加し、抗－Ｂｅｃｌｉｎ After treating test samples at 10, 25, 50, and 100 μg/mL, 20 and 100 μg/mL of lipid polysaccharide (LPS) were added and anti-Beclin

１抗体（Ａｂｃａｍ）およびＬＣ３Ｂ－抗体（Ｃｅｌｌ Ｓｉｇｎａｌｉｎｇ）をそれぞれ用いたイムノブロッティング試験により、Ｂｅｃｌｉｎ １とＬＣ３Ｂ（オートファジーマーカー）の発現を確認した。 The expression of Beclin 1 and LC3B (autophagy marker) was confirmed by immunoblotting tests using 1 antibody (Abcam) and LC3B-antibody (Cell Signaling), respectively.

ＣｈｅｍｉＤｏｃＴＭＭＰＩｍａｇｉｎｇＳｙｓｔｅｍ（Ｂｉｏｒａｄ）で得られた感光性フィルムをスキャンして、Ｂｅｃｌｉｎ １およびＬＣ３Ｂの発現レベルを定量化した。 Beclin 1 and LC3B expression levels were quantified by scanning the resulting light-sensitive films with a ChemiDoc ™ MP Imaging System (Biorad).

４－２．試験結果
表７に示すように、試験試料と１００μｇ／ｍＬの脂質多糖類（ＬＰＳ）で処理した試験群がＬＣ３Ｂ－１とＢｅｃｌｉｎ１の発現に対して用量依存的に増加する効果を示すことが確認された。 4-2. Test results As shown in Table 7, it was confirmed that the test sample and the test group treated with 100 μg/mL lipid polysaccharide (LPS) showed a dose-dependent increase effect on the expression of LC3B-1 and Beclin1. was done.

Figure 2023519549000007
Figure 2023519549000007

実験例５．関節炎抑制効果（ｉｎ ｖｉｖｏ）
本発明の抽出物の関節炎抑制効果を確認するために、関節炎誘導性ラット動物モデルを用いた動物モデル実験を、当技術分野における既知の手順に従って行った。 Experimental example 5. Arthritis suppression effect (in vivo)
In order to confirm the anti-arthritis effect of the extract of the present invention, animal model experiments using arthritis-induced rat animal model were performed according to procedures known in the art.

５－１．試験手順
ＭＩＡ（ヨード酢酸モノナトリウム）誘導性変形性関節炎ラットモデルに対する試験試料の効能を評価するために、韓国、ソウルＳＴ．ソウル聖母病院カトリック大学に位置する「関節免疫疾患Ｔ２Ｂセンター（院長パク・ソンファン）」にて、以下の試験を行った。 5-1. TEST PROCEDURES Seoul, Korea, ST. The following tests were conducted at the ``T2B Center for Arthritis and Immunopathies (Director Park Seong-hwan)'' located at Catholic University, Seoul St. Mary's Hospital.

５－１－１．試験プロトコル
５－１－１－１．動物モデル試験手順
（１）試験動物：１２時間間隔で明暗サイクル（０８：００～２０：００）、温度２１±２℃、相対湿度５０±２０％を維持しながら、ラット（オスウィスタラット、中央研究所動物、ソウル、韓国、７～８週齢、２００～２５０ｇ）をポリスルホン製ケージ（ケージ当たり２～３匹のマウス）で適切に管理された飼育室で飼育し、周囲の環境に順応させた。 5-1-1. test protocol
5-1-1-1. Animal model test procedure (1) Test animals: rats (male Wistar rats, central Laboratory animals, Seoul, Korea, 7-8 weeks old, 200-250 g) were housed in polysulfone cages (2-3 mice per cage) in well-controlled housing and allowed to acclimate to the surrounding environment. rice field.

試験方法：３ｍｇ／ｋｇのヨウ素酢酸ナトリウム（ＭＩＡ、Ｉ２５１２、Ｓｉｇｍａ、Ｐｏｏｌｅ、ＵＫ）を、実験当日（０日）に６０ｍｇ／ｍｌの濃度に達するように注射食塩水に溶解した。各群に分けた後、実験動物を麻酔室に入れ、ジエチルエーテルで麻酔させた。変形性関節症を誘発するために、１ｃｃシリンジ（２６．５ゲージ）を用いて、膝蓋靱帯を通して５０μＬのＭＩＡ（３ｍｇ／ｂｏｄｙ）を右膝関節に注射した。
（２）試験試料：実施例で調製した本発明の抽出物
（３）陽性対照群：セレコシブ（Ｃｅｌｅｃｏｘｉｂ）（ハンリム製薬、ソウル、韓国）
（４）治療経路：変形性関節炎誘発後３日目に経口投与（１日１回）
（５）試験群の設定：表８参照。 Test method: 3 mg/kg sodium iodoacetate (MIA, 12512, Sigma, Poole, UK) was dissolved in saline for injection to reach a concentration of 60 mg/ml on the day of the experiment (day 0). After being divided into each group, the experimental animals were put into an anesthesia chamber and anesthetized with diethyl ether. A 1 cc syringe (26.5 gauge) was used to inject 50 μL of MIA (3 mg/body) into the right knee joint through the patellar ligament to induce osteoarthritis.
(2) Test sample: the extract of the present invention prepared in Example (3) Positive control group: Celecoxib (Hanlim Pharmaceutical, Seoul, Korea)
(4) Treatment route: oral administration (once a day) on day 3 after induction of osteoarthritis
(5) Study group setting: see Table 8.

５－１－１－２．投与経路および試験期間
（１）投与経路
ＭＩＡで変形性関節症を誘発した後、試験試料をビヒクル（食塩水）で処方された用量に応じて均質化し、１日１回１ｍＬの試験試料を経口投与し、試験試料処理群（Ｇ２、Ｇ３）を調製した。 5-1-1-2. Route of administration and test period (1) Route of administration
After induction of osteoarthritis with MIA, the test samples were homogenized in vehicle (saline) according to the prescribed dose, and 1 mL of the test sample was administered orally once daily, and the test sample treatment groups (G2, G3) was prepared.

陰性対照群（Ｇ１）は、ビヒクルのみで処理し、試験物質投与により試料スケジュールに従って１日１回経口投与した。 The negative control group (G1) was treated with vehicle only and was orally dosed once daily according to the sample schedule with test substance administration.

陽性対照群（Ｇ４）は、処方された用量に従ってビヒクルに均質化し、１日１回経口投与した。 The positive control group (G4) was homogenized in vehicle according to the prescribed dose and administered orally once daily.

（２）試験期間
２４匹のラットを６匹当たり４つの群に分け、試験試料と陽性対照群物質を所定の時間に経口投与した。 (2) Test period
Twenty-four rats were divided into 4 groups of 6 rats and orally administered test samples and positive control group substances at given times.

Figure 2023519549000008
Figure 2023519549000008

５－２．評価内容
５－２－１．痛みの閾値の測定
５－２－１－１．痛みの閾値の測定方法
痛みの閾値（侵害受容潜伏期、閾値）は、痛みの閾値を測定するためのｖｏｎ Ｆｒｅｅｓｔｙｌｅ評価方法に従い、一定期間、雄ウィスタラットの肢に加えられる力を徐々に増加させる装置である、ダイナミックプランター・エステシオメータ（Ｕｇｏ Ｂａｓｉｌｅ， ３７４００， Ｃｏｍｅｒｉｏ， Ｉｔａｌｙ）を用いて測定を行った（Ｋｗｏｎ ＪＹ ｅｔ ａｌ．， Ｓｃｉ Ｒｅｐ． ２０１８ Ｓｅｐ １４；８（１）：１３８３２）。 5-2. Evaluation content
5-2-1. Measurement of pain threshold
5-2-1-1. Method for Measuring Pain Threshold Pain threshold (nociceptive latency, threshold) is measured according to the von Freestyle assessment method for measuring pain threshold, using a device that gradually increases the force applied to the paw of male Wistar rats over a period of time. (Kwon JY et al., Sci Rep. 2018 Sep 14;8(1):13832).

測定前に、動物を金網ベンチ付きアクリルボックスに入れ、５分間順応させた。 Animals were placed in acrylic boxes with wire mesh benches and allowed to acclimatize for 5 minutes prior to measurements.

各動物の右後肢の中央に金属製フィラメントを用いて１０秒間にわたって０～５０ｇのゆっくりとした力を加え、動物が肢を引っ込める肢の引っ込め行動を示す体重を測定し、痛みの閾値を測定した。 A slow force of 0-50 g was applied to the middle of each animal's right hind paw using a metal filament for 10 seconds, and the animal exhibited a paw withdrawal behavior in which the animal withdrew the paw.Weighed and measured the pain threshold. .

組織の損傷を避けるために、カットオフ閾値（ｃｕｔ－ｏｆｆ ｔｈｒｅｓｈｏｌｄ）を５０ｇに設定し、測定時間をＭＩＡ治療による変形性関節症の誘発日の前日に設定し、正常対照群（Ｇ１）、試験試料群（Ｇ２、Ｇ３）および陽性対照群（Ｇ４）の基準線値を算出し、基準線（３日目）で同じ値が得られた。 To avoid tissue damage, the cut-off threshold was set to 50 g, the measurement time was set to the day before the induction of osteoarthritis by MIA treatment, normal control group (G1), test Baseline values for sample groups (G2, G3) and positive control group (G4) were calculated and the same values were obtained at baseline (day 3).

試験試料の処理前（３日目）同じ値を測定し、試験試料をラットの関節腔内に投与し、週１回特定時間に値を測定した。 The same values were measured before treatment of test samples (day 3), test samples were administered intra-articularly to rats and values were measured once a week at specified times.

痛みの閾値の試験結果は、（ａ）肢引っ込め潜期（秒）および（ｂ）肢引っ込め閾値（ｇ）に従って計算した。 Pain threshold test results were calculated according to (a) paw withdrawal latency (seconds) and (b) paw withdrawal threshold (g).

５－２－１－２．痛みの閾値測定試験の結果
痛みの測定試験の結果、１００および１５０ｍｇ／ｋｇの試験試料で処理した試験試料群は、用量依存的にビヒクルで処理した陰性対照群と比較して、強力な痛み抑制効果を示すことが確認された（表９－１０）。 5-2-1-2. Results of the Pain Threshold Measurement Test Results of the pain measurement test showed that the test sample groups treated with 100 and 150 mg/kg test sample dose-dependently exhibited potent pain suppression compared to the vehicle-treated negative control group. It was confirmed that the effect was exhibited (Table 9-10).

Figure 2023519549000009
Figure 2023519549000009

Figure 2023519549000010
Figure 2023519549000010

５－２－２．体重負荷測定に対する試験
５－２－２－１．体重負荷の測定
正常な後肢（左）と関節炎誘発後肢（右）間の体重の変化（または体重分布）を測定するために、文献（Ｋｗｏｎ ＪＹ ｅｔ ａｌ．，Ｓｃｉ Ｒｅｐ．２０１８ Ｓｅｐ １４；８（１）：１３８３２）に記載の方法に従って試験装置（モデル６００、ＩＩＴＣ、ＵＳＡ）を用いて両後肢の負荷を測定した。 5-2-2. Testing for weight bearing measurements
5-2-2-1. Measurement of Weight Bearing To measure the change in body weight (or weight distribution) between the normal hindlimb (left) and the arthritic hindlimb (right), Kwon JY et al., Sci Rep. 2018 Sep 14; 1):13832), the loading of both hind limbs was measured using a test apparatus (model 600, IITC, USA).

動物の肢の位置によって荷重が変わる可能性があるので、試験動物をホルダーに正しく配置させ、両肢が対称になるように固定する。なるべくあり得る誤差を減らすために特定人が固定する。 Since the position of the animal's limbs can change the load, the test animal is positioned correctly in the holder and fixed so that both limbs are symmetrical. Fixed by a specific person to reduce possible errors as much as possible.

各動物がホルダーに正確に配置すると、機械を作動させ、各群の体重負荷を１回の測定につき５秒間２回測定した。 Once each animal was correctly placed in the holder, the machine was activated and each group's weight bearing was measured twice for 5 seconds per measurement.

各試験結果の平均値は、各肢の体重負荷（ｇ）でデジタル化した。 The mean value of each test result was digitized with the weight bearing (g) of each limb.

ＭＩＡ治療前の基準値（０日目）を得た後、正常対照群（Ｇ１）、試験試料群（Ｇ２、Ｇ３）および陽性対照群（Ｇ４）の体重負荷を週２回特定時間に試験試料測定前３日前に決定した（３日目）。 After obtaining the baseline value before MIA treatment (day 0), the weight bearing of the normal control group (G1), the test sample groups (G2, G3) and the positive control group (G4) was carried out twice a week at specified times. Determined 3 days before measurement (day 3).

体重負荷測定の試験結果を下記数式１に従って各体重負荷率に変換した。 The weight bearing test results were converted into weight bearing ratios according to Equation 1 below.

［数式１］
重量比（％）＝｛右後肢の重量／（右後肢の重量＋左後肢の重量）｝×１００ [Formula 1]
Weight ratio (%) = {weight of right hind limb/(weight of right hind limb + weight of left hind limb)} × 100

５－２－２－２．体重負荷試験の結果
表１１に示すように、試験試料群は、陰性対照群と比較して、両肢のバランス能力が大幅に向上されることが確認された。 5-2-2-2. Weight bearing test results As shown in Table 11, it was confirmed that the test sample group had significantly improved balance ability in both limbs compared to the negative control group.

Figure 2023519549000011
Figure 2023519549000011

５－２－３．骨損傷抑制試験（組織学的解析、マイクロＣＴ）
本発明の抽出物の骨損傷抑制効果を決定するために、文献（Ｋｗｏｎ ＪＹ ｅｔ ａｌ．，Ｓｃｉ．Ｒｅｐ．２０１８ Ｓｅｐ １４；８（１）：１３８３２）に記載された公知の方法に従って組織学的解析を行った。 5-2-3. Bone injury inhibition test (histological analysis, micro CT)
To determine the bone damage inhibitory effect of the extract of the present invention, histological analysis was performed according to known methods described in the literature (Kwon JY et al., Sci. Rep. 2018 Sep 14;8(1):13832). I did the analysis.

５－２－３－１．変形性関節症による骨損傷抑制効果（組織学的解析、マイクロＣＴ）
本発明の抽出物の変形性関節症による骨損傷に対する抑制効果を確認するために、犠牲にしたラット（雄ウィスタラット）の右膝関節にＭＩＡと試験試料を投与し、ホルマリンで固定した。 5-2-3-1. Effect of suppressing bone damage due to osteoarthritis (histological analysis, micro-CT)
To confirm the inhibitory effect of the extract of the present invention on bone damage caused by osteoarthritis, MIA and test samples were administered to the right knee joint of sacrificed rats (male Wistar rats) and fixed with formalin.

３匹のラットからなる各群において、膝関節の大腿骨領域周辺の骨損傷の程度は、Ｘ線源（７０ｋＶ、１４２ｕＡ、ＡＩ ０．５ｍｍフィルター、回転ステップ０．６°）と動物用スキャナー（ＳＫＹＳＣＡＮ１２７２ ｅｘ－ｖｉｖｏ ｍｉｃｒｏ－ＣＴ， Ｂｒｕｋｅｒ ｍｉｃｒｏ ＣＴ， Ｂｅｌｇｉｕｍ）、断面形成（ＮＲｅｃｏｎ）、断面回転（Ｄａｔａ Ｖｉｅｗｅｒ）、データ解析（ＣＴＡＮ）、ボリュームレンダリング生成（ＣＴＶｏｘ）、および表面レンダリング（ＣＴＡＮ ＋ ＣＴＶｏｌ）を含むピクセル解像度１５μｍでマイクロＣＴ撮影を行った。 In each group of 3 rats, the extent of bone damage around the femoral region of the knee joint was assessed using an X-ray source (70 kV, 142 uA, AI 0.5 mm filter, rotation step 0.6°) and an animal scanner ( SKYSCAN1272 ex-vivo micro-CT, Bruker micro CT, Belgium), section formation (NRecon), section rotation (Data Viewer), data analysis (CTAN), volume rendering generation (CTVox), and surface rendering (CTAN + CTVol). Micro-CT imaging was performed at an included pixel resolution of 15 μm.

５－２－３－２．組織学的解析の試験結果（マイクロ－ＣＴ）
表１２に示すように、１００および１５０ｍｇ／ｋｇの試験試料で処理した試験試料群がマイクロＣＴ撮影の試験結果を通じて陰性対象群（ビヒクル群）と比べて強力な骨損傷抑制効果を示すことが確認された。 5-2-3-2. Histological analysis test results (micro-CT)
As shown in Table 12, it was confirmed that the test sample group treated with 100 and 150 mg/kg test sample exhibited a stronger bone damage inhibitory effect than the negative control group (vehicle group) through micro-CT imaging test results. was done.

Figure 2023519549000012
Figure 2023519549000012

５－２－４．骨損傷抑制試験（組織病理学的解析）
本発明の抽出物の骨損傷抑制効果を決定するために、文献（Ｋｗｏｎ ＪＹ ｅｔ ａｌ．，Ｓｃｉ Ｒｅｐ．２０１８ Ｓｅｐ．１４；８（１）：１３８３２）に公知された方法に従って以下の組織病理学的解析を行った。 5-2-4. Bone injury inhibition test (histopathological analysis)
To determine the bone damage inhibitory effect of the extract of the present invention, the following histopathology was performed according to the method known in the literature (Kwon JY et al., Sci Rep. 2018 Sep. 14;8(1):13832). A systematic analysis was performed.

５－２－３－１．変形性関節症による骨損傷抑制効果（組織病理学的解析）
本発明の抽出物の変形性関節症による骨損傷に対する抑制効果を確認するために、犠牲にしたラット（雄ウィスタラット）の右膝関節にＭＩＡと試験試料を投与し、ホルマリンで固定されたラットの右膝関節をスライスし、Ｓａｆｒａｎｉｎ Ｏで染色した。 5-2-3-1. Suppressive effect on bone damage caused by osteoarthritis (histopathological analysis)
In order to confirm the inhibitory effect of the extract of the present invention on bone damage caused by osteoarthritis, MIA and a test sample were administered to the right knee joint of sacrificed rats (male Wistar rats) and the rats were fixed with formalin. right knee joint was sliced and stained with Safranin O.

組織病理学的解析は、膝関節の大腿骨領域（ｘ２００倍）を撮影することによって行った。試験結果は、総マンキンスコア（Ｂｕｌｓｔｒａ ＳＫら、１９８９、Ｃｌｉｎ Ｏｒｔｈｏｐ Ｒｅｌａｔ Ｒｅｓ：２９４－３０２）およびＯＡＲＳＩスコア（Ｐｒｉｔｚｋｅｒ ＫＰＨら、２００６、Ｏｓｔｅｏａｒｔｈｒｉｔｉｓ Ｃａｒｔｉｌａｇｅ １４ ：１３－２９）を含む公知の方法に従って計算および評価した。 Histopathological analysis was performed by imaging the femoral region of the knee joint (x200 magnification). Test results are calculated and evaluated according to known methods, including total Mankin score (Bulstra SK et al., 1989, Clin Orthop Relat Res: 294-302) and OARSI score (Pritzker KPH et al., 2006, Osteoarthritis Cartilage 14:13-29). bottom.

５－２－３－２．組織病理学的解析試験の結果
表１３（総マンキンスコア法）および表１４（ＯＡＲＳＩスコア）からわかるように、１００および１５０ｍｇ／ｋｇの試験試料で処理した試験試料群は、組織病理学的解析結果を通じた陰性対照群群（ビヒクル群）に比べて骨損傷に対する強力な抑制効果を示すことが確認された。 5-2-3-2. Histopathological analysis test results As can be seen from Table 13 (Total Mankin Score method) and Table 14 (OARSI score), the test sample groups treated with 100 and 150 mg/kg test sample showed good results in histopathological analysis. It was confirmed that it exhibited a strong inhibitory effect on bone damage compared to the negative control group (vehicle group) through the test.

Figure 2023519549000013
Figure 2023519549000013

Figure 2023519549000014
Figure 2023519549000014

統計解析
すべてのデータは、平均および標準偏差（平均±ＳＤ）で表され、ＧｒａｐｈＰａｄ ＰＲＩＳＭバージョン５．０（ＵＳＡ）解析プログラムにより、二元配置分散分析（ｔｗｏ－ｗａｙ ＡＮＯＶＡ）、一元配置分散分析（ｏｎｅ－ｗａｙ ＡＮＯＶＡ）を用いて統計的有意性検証が有意であると判断（Ｐ＜０．０５）された。 Statistical analysis All data are expressed as mean and standard deviation (mean ± SD) and analyzed by GraphPad PRISM version 5.0 (USA) analysis program, two-way ANOVA, one-way analysis of variance ( Statistical significance testing was determined to be significant (P<0.05) using a one-way ANOVA).

以下、賦形剤の剤形化方法および種類について説明するが、本発明がこれに限定されるものではない。代表的な調製例は、以下のように説明される。 The formulation method and types of excipients will be described below, but the present invention is not limited thereto. A representative preparation is illustrated as follows.

注射液の調製
ＷＩＮ－１００１Ｘエキス：１００ｍｇ
メタ重亜硫酸ナトリウム：３．０ｍｇ
メチルパラベン：０．８ｍｇ
プロピルパラベン：０．１ｍｇ
注入用蒸留水：最適量
有効成分を溶解させ、ｐＨを約７．５に調整した後、全成分を２ｍｌアンプルに充填し、従来の注射剤調製法により滅菌して注射剤を調製した。 Preparation of injection solution WIN-1001X extract: 100 mg
Sodium metabisulfite: 3.0 mg
Methylparaben: 0.8mg
Propyl paraben: 0.1 mg
Distilled water for injection: optimum amount After dissolving the active ingredient and adjusting the pH to about 7.5, all the ingredients were filled into a 2 ml ampoule and sterilized by a conventional injection preparation method to prepare an injection.

散剤の調製
ＷＩＮ－１００２Ｘエキス：５００ｍｇ
トウモロコシデンプン：１００ｍｇ
ラクトース：１００ｍｇ
タルク：１０ｍｇ
上記の成分を混合し、密封パッケージに充填することにより散剤の製剤を調製した。 Preparation of powder WIN-1002X extract: 500 mg
Corn starch: 100 mg
Lactose: 100mg
Talc: 10 mg
A powder formulation was prepared by mixing the above ingredients and filling in a sealed package.

錠剤の調製
ＷＩＮ－１００３Ｘエキス：２００ｍｇ
トウモロコシデンプン：１００ｍｇ
ラクトース：１００ｍｇ
ステアリン酸マグネシウム：最適量
前記の成分を混合し、錠剤化することにより錠剤の製剤を調製した。 Preparation of tablets WIN-1003X extract: 200 mg
Corn starch: 100 mg
Lactose: 100mg
Magnesium stearate: optimal amount A tablet formulation was prepared by mixing and tableting the above ingredients.

カプセルの調製
ＷＩＮ－１００４Ｘエキス：１００ｍｇ
ラクトース：５０ｍｇ
トウモロコシデンプン：５０ｍｇ
タルク：２ｍｇ
ステアリン酸マグネシウム：最適量
上記の成分を混合し、ゼラチンカプセルを従来のゼラチン製造方法により充填して錠剤の製剤を調製した。 Preparation of Capsules WIN-1004X Extract: 100mg
Lactose: 50mg
Corn starch: 50 mg
Talc: 2mg
Magnesium Stearate: Optimum Amount Tablet formulations were prepared by mixing the above ingredients and filling gelatin capsules by conventional gelatin manufacturing methods.

液体の調製
ＷＩＮ－１００５Ｘエキス：１０００ｍｇ
糖：２０ｇ
多糖類：２０ｇ
レモン風味：２０ｇ
有効成分を溶解させた後、全成分を１０００ｍｌのアンプルに充填し、従来の液体の調製法で滅菌し、調製液を調製した。 Liquid preparation WIN-1005X extract: 1000 mg
Sugar: 20g
Polysaccharides: 20g
Lemon flavor: 20g
After dissolving the active ingredient, all the ingredients were filled into a 1000 ml ampoule and sterilized by a conventional liquid preparation method to prepare a preparation solution.

健康食品の製造
ＷＩＮ－１００１Ｘエキス：１０００ｍｇ
ビタミン混合物：最適量
ビタミンＡアセテート：７０ｇ
ビタミンＥ：１．０ｍｇ
ビタミンＢ１０：１３ｍｇ
ビタミンＢ２：０．１５ｍｇ
ビタミンＢ６：０．５ｍｇ
ビタミンＢ１：２０．２ｇ
ビタミンＣ：１０ｍｇ
ビオチン：１０ｇ
アミドニコチン酸：１．７ｍｇ
葉酸：５０ｇ
パントテン酸カルシウム：０．５ｍｇ
ミネラル混合物：最適量
硫酸第一鉄：１．７５ｍｇ
酸化亜鉛：０．８２ｍｇ
炭酸マグネシウム：２５．３ｍｇ
リン酸一カリウム：１５ｍｇ
リン酸二カルシウム：５５ｍｇ
クエン酸カリウム：９０ｍｇ
炭酸カルシウム：１００ｍｇ
塩化マグネシウム：２４．８ｍｇ
上記のビタミンとミネラルの混合物は、あらゆる方法で多様にできる。このような変形は、本発明の精神および範囲から逸脱するとみなされるべきではない。 Production of health food WIN-1001X extract: 1000mg
Vitamin mixture: optimal amount Vitamin A acetate: 70g
Vitamin E: 1.0 mg
Vitamin B10 : 13mg
Vitamin B2 : 0.15mg
Vitamin B6 : 0.5 mg
Vitamin B1 : 20.2g
Vitamin C: 10mg
Biotin: 10g
Amidonicotinic acid: 1.7 mg
Folic acid: 50g
Calcium pantothenate: 0.5 mg
Mineral mixture: optimum amount Ferrous sulfate: 1.75 mg
Zinc oxide: 0.82 mg
Magnesium carbonate: 25.3 mg
Monopotassium phosphate: 15 mg
Dicalcium phosphate: 55 mg
Potassium citrate: 90mg
Calcium carbonate: 100 mg
Magnesium chloride: 24.8 mg
The above vitamin and mineral mixtures can be varied in many ways. Such variations should not be considered a departure from the spirit and scope of the invention.

健康飲料の調製
ＷＩＮ－１００２Ｘエキス：１０００ｍｇ
クエン酸：１０００ｍｇ
オリゴ糖：１００ｇ
アプリコット濃度：２ｇ
タウリン：１ｇ
蒸留水：９００ｍｌ
有効成分を溶解させて混合し、８５℃で１時間撹拌した後、濾過した後、全成分を１０００ｍｌアンプルに充填し、既存の健康飲料の調製方法で滅菌し、健康飲料の製剤を調製した。 Preparation of health drink WIN-1002X extract: 1000 mg
Citric acid: 1000mg
Oligosaccharide: 100g
Apricot concentration: 2g
Taurine: 1g
Distilled water: 900ml
The active ingredients were dissolved and mixed, stirred at 85° C. for 1 hour, filtered, and then filled into a 1000 ml ampoule and sterilized by the existing health drink preparation method to prepare a health drink formulation.

したがって、上述の本発明は多様な方法で変形可能であることが明らかである。このような変形は、本発明の精神および範囲から逸脱するものと見なされてはならず、当業者にとって自明であるような全ての変形は、下記特許請求の範囲内に含まれることが意図されている。 It is therefore evident that the invention described above can be varied in many ways. Such variations should not be regarded as a departure from the spirit and scope of the invention, and all such variations as would be obvious to one skilled in the art are intended to be included within the scope of the following claims. ing.

本発明に記載されているように、本発明は、竜眼肉、藁本およびオンジの混合生薬抽出物を含む経口用医薬組成物を提供し、本発明者らは、炎症に関与するサイトカイン（ＲＰＬＰＯ、ＴＳＬＰ、ＧＭ－ＣＳＦ、およびＩＬ－１ベータ）の発現抑制試験（実験例１）；ＨＴ－２９およびＴＨＰ－１細胞に対する細胞生存率試験（ｉｎ ｖｉｔｒｏ、実験例２）；ＴＨＰ－１細胞における抗炎症活性（ｉｎ ｖｉｔｒｏ、実験例３）；オートファジー活性抑制効果（ｉｎ ｖｉｔｒｏ、実験例４）などのｉｎ ｖｉｔｒｏ実験だけでなく、関節炎誘発ラット動物モデルを用いた関節炎抑制効果（ｉｎ ｖｉｖｏ、実験例５）のようなｉｎ ｖｉｖｏ実験を行うことにより、本発明の混合組成物の抗炎症／抗リウマチ効果が強力であることを立証した。したがって、本発明の混合抽出物が経口用医薬組成物の形態として炎症疾患および関節炎疾患の改善または治療に非常に有用であることを確認した。 As described in the present invention, the present invention provides an oral pharmaceutical composition comprising a mixed herbal extract of longan, straw and onji, and the inventors have found cytokines involved in inflammation (RPLPO, TSLP, GM-CSF, and IL-1 beta) expression suppression test (Experimental Example 1); cell viability test on HT-29 and THP-1 cells (in vitro, Experimental Example 2); Not only in vitro experiments such as inflammatory activity (in vitro, Experimental Example 3); autophagy activity inhibitory effect (in vitro, Experimental Example 4), but also arthritis inhibitory effect (in vivo, Experimental Example By conducting in vivo experiments such as 5), the anti-inflammatory/anti-rheumatic effect of the mixed composition of the present invention was proved to be potent. Therefore, it was confirmed that the mixed extract of the present invention, in the form of an oral pharmaceutical composition, is very useful for ameliorating or treating inflammatory diseases and arthritic diseases.

Claims (8)

皮膚炎、アトピー性皮膚炎、結膜炎、歯周炎、鼻炎、中耳炎、咽頭痛、扁桃炎、肺炎、胃潰瘍、胃炎、クローン病、大腸炎、痔、痛風、リウマチ熱、狼瘡、線維筋痛症、腱炎、腱鞘炎、腱周囲炎、筋炎、肝炎、膀胱炎、腎炎、シェーグレン症候群、慢性炎症および急性炎症によって引き起こされる掻痒症の群から選択される炎症性疾患を予防および治療するための竜眼肉（Ｌｏｎｇａｎａｅ Ａｒｉｌｌｕｓ）、藁本（Ｌｉｇｕｓｔｉｃｉ Ｔｅｎｕｉｓｓｉｍｉ Ｒｈｉｚｏｍａ）およびオンジ（Ｐｏｌｙｇａｌａｅ ｒａｄｉｘ）の混合生薬抽出物を有効成分として含む経口用医薬組成物。 Dermatitis, atopic dermatitis, conjunctivitis, periodontitis, rhinitis, otitis media, sore throat, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, hemorrhoids, gout, rheumatic fever, lupus, fibromyalgia, Longanae for the prevention and treatment of inflammatory diseases selected from the group of tendonitis, tenosynovitis, peritendinitis, myositis, hepatitis, cystitis, nephritis, Sjögren's syndrome, pruritus caused by chronic inflammation and acute inflammation Arillus), straw book (Ligustici Tenuissimi Rhizoma) and onji (Polygalae radix) mixed herbal extracts as active ingredients. 前記混合生薬抽出物は、（ａ）０．０１－１００：０．０１－１００：０．０１－１００重量部（ｗ／ｗ）の範囲の竜眼肉、藁本およびオンジの乾燥重量（ｗ／ｗ）を基準とした混合比を有する竜眼肉、藁本およびオンジの混合生薬抽出物、または（ｂ）０．０１－１００：０．０１－１００：０．０１－１００重量部（ｗ／ｗ）の範囲の竜眼肉、藁本およびオンジの乾燥重量（ｗ／ｗ）を基準とした混合比を有する竜眼肉、藁本およびオンジの各抽出物の混合物であることを特徴とする、請求項１に記載の経口用医薬組成物。 The mixed crude drug extract contains (a) the dry weight (w/w) of longan, straw and onji in the range of 0.01-100:0.01-100:0.01-100 parts by weight (w/w) ), or (b) 0.01-100:0.01-100:0.01-100 parts by weight (w/w) 2. The method according to claim 1, characterized in that it is a mixture of extracts of Longan, Waramoto and Onji with a mixing ratio based on the dry weight (w/w) of Longan, Waramoto and Onji within a range. Oral pharmaceutical composition. 前記抽出物は、水、Ｃ１－Ｃ４低級アルキルアルコール、例えば、メタノール、エタノール、プロパノール、ブタノール、アセトン、酢酸エチル、クロロホルム、ヘキサン、ブチレングリコール、プロピレングリコールまたはグリセリンから選択される１つ以上の溶媒で抽出されることを特徴とする、請求項１に記載の経口用医薬組成物。 The extract is water, C 1 -C 4 lower alkyl alcohols such as one or more selected from methanol, ethanol, propanol, butanol, acetone, ethyl acetate, chloroform, hexane, butylene glycol, propylene glycol or glycerin. Oral pharmaceutical composition according to claim 1, characterized in that it is extracted with a solvent. 皮膚炎、アトピー性皮膚炎、結膜炎、歯周炎、鼻炎、中耳炎、咽頭痛、扁桃炎、肺炎、胃潰瘍、胃炎、クローン病、大腸炎、痔、痛風、リウマチ熱、狼瘡、線維筋痛症、腱炎、腱鞘炎、腱周囲炎、筋炎、肝炎、膀胱炎、腎炎、シェーグレン症候群、慢性炎症および急性炎症によって引き起こされる掻痒症の群から選択される炎症性疾患を予防および改善するための竜眼肉（Ｌｏｎｇａｎａｅ Ａｒｉｌｌｕｓ）、藁本（Ｌｉｇｕｓｔｉｃｉ Ｔｅｎｕｉｓｓｉｍｉ Ｒｈｉｚｏｍａ）およびオンジ（Ｐｏｌｙｇａｌａｅ ｒａｄｉｘ）の混合生薬抽出物を有効成分として含む健康機能食品。 Dermatitis, atopic dermatitis, conjunctivitis, periodontitis, rhinitis, otitis media, sore throat, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, hemorrhoids, gout, rheumatic fever, lupus, fibromyalgia, Longanae for preventing and ameliorating inflammatory diseases selected from the group of tendonitis, tenosynovitis, peritendinitis, myositis, hepatitis, cystitis, nephritis, Sjögren's syndrome, pruritus caused by chronic inflammation and acute inflammation Arillus), straw book (Ligustici Tenuissimi Rhizoma) and onji (Polygalae radix) mixed crude drug extract as an active ingredient. 前記健康機能食品は、散剤、顆粒剤、錠剤、カプセル剤、丸剤、懸濁剤、乳剤、シロップ、ティーバッグ、浸出茶、または飲料の形態で提供されることを特徴とする、請求項４に記載の健康機能食品。 [Claim 4] The health functional food is provided in the form of powders, granules, tablets, capsules, pills, suspensions, emulsions, syrups, tea bags, infused teas, or beverages. Health functional food described in . 皮膚炎、アトピー性皮膚炎、結膜炎、歯周炎、鼻炎、中耳炎、咽頭痛、扁桃炎、肺炎、胃潰瘍、胃炎、クローン病、大腸炎、痔、痛風、リウマチ熱、狼瘡、線維筋痛症、腱炎、腱鞘炎、腱周囲炎、筋炎、肝炎、膀胱炎、腎炎、シェーグレン症候群、慢性炎症および急性炎症によって引き起こされる掻痒症の群から選択される炎症性疾患を予防または改善するための竜眼肉（Ｌｏｎｇａｎａｅ Ａｒｉｌｌｕｓ）、藁本（Ｌｉｇｕｓｔｉｃｉ Ｔｅｎｕｉｓｓｉｍｉ Ｒｈｉｚｏｍａ）およびオンジ（Ｐｏｌｙｇａｌａｅ ｒａｄｉｘ）の混合生薬抽出物を有効成分としてまたは主要成分として含む健康補助食品。 Dermatitis, atopic dermatitis, conjunctivitis, periodontitis, rhinitis, otitis media, sore throat, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, hemorrhoids, gout, rheumatic fever, lupus, fibromyalgia, Longanae for preventing or ameliorating inflammatory diseases selected from the group of tendonitis, tenosynovitis, peritendinitis, myositis, hepatitis, cystitis, nephritis, Sjögren's syndrome, pruritus caused by chronic inflammation and acute inflammation A health supplement comprising mixed herbal extracts of Ligustici Tenuissimi Rhizoma, Ligustici Tenuissimi Rhizoma and Polygalae radix as active ingredients or as major ingredients. 竜眼肉（Ｌｏｎｇａｎａｅ Ａｒｉｌｌｕｓ）、藁本（Ｌｉｇｕｓｔｉｃｉ Ｔｅｎｕｉｓｓｉｍｉ Ｒｈｉｚｏｍａ）およびオンジ（Ｐｏｌｙｇａｌａｅ ｒａｄｉｘ）の有効量の混合生薬抽出物またはその薬学的に許容される担体を哺乳動物に経口投与する段階を含む、哺乳動物の皮膚炎、アトピー性皮膚炎、結膜炎、歯周炎、鼻炎、中耳炎、咽頭痛、扁桃炎、肺炎、胃潰瘍、胃炎、クローン病、大腸炎、痔、痛風、リウマチ熱、狼瘡、線維筋痛症、腱炎、腱鞘炎、腱周囲炎、筋炎、肝炎、膀胱炎、腎炎、シェーグレン症候群、慢性炎症および急性炎症によって引き起こされる掻痒症の群から選択される炎症性疾患を治療または改善する方法。 orally administering to the mammal an effective amount of a mixed herbal extract of Longanae Arillus, Ligustici Tenuissimi Rhizoma and Polygalae radix or a pharmaceutically acceptable carrier thereof. Dermatitis, atopic dermatitis, conjunctivitis, periodontitis, rhinitis, otitis media, sore throat, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, hemorrhoids, gout, rheumatic fever, lupus, fibromyalgia, A method of treating or ameliorating an inflammatory disease selected from the group of tendonitis, tenosynovitis, peritendinitis, myositis, hepatitis, cystitis, nephritis, Sjögren's syndrome, chronic inflammation and pruritus caused by acute inflammation. 有効成分であって、皮膚炎、アトピー性皮膚炎、結膜炎、歯周炎、鼻炎、中耳炎、咽頭痛、扁桃炎、肺炎、胃潰瘍、胃炎、クローン病、大腸炎、痔、痛風、リウマチ熱、狼瘡、線維筋痛症、腱炎、腱鞘炎、腱周囲炎、筋炎、肝炎、膀胱炎、腎炎、シェーグレン症候群、慢性炎症および急性炎症によって引き起こされる掻痒症の群から選択される炎症性疾患を治療または改善するために使用される経口用製剤を調製するための 竜眼肉（Ｌｏｎｇａｎａｅ Ａｒｉｌｌｕｓ）、藁本（Ｌｉｇｕｓｔｉｃｉ Ｔｅｎｕｉｓｓｉｍｉ Ｒｈｉｚｏｍａ）およびオンジ（Ｐｏｌｙｇａｌａｅ ｒａｄｉｘ）の混合生薬抽出物の使用。 The active ingredient is dermatitis, atopic dermatitis, conjunctivitis, periodontitis, rhinitis, otitis media, sore throat, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, hemorrhoids, gout, rheumatic fever, lupus. , fibromyalgia, tendonitis, tenosynovitis, peritendinitis, myositis, hepatitis, cystitis, nephritis, Sjögren's syndrome, chronic inflammation and pruritus caused by acute inflammation. Use of a mixed herbal extract of Longanae Arillus, Ligustici Tenuissimi Rhizoma and Polygalae radix for preparing an oral formulation used for
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